Synthesis of an antiviral compound

ABSTRACT

The present disclosure provides processes for the preparation of a compound of formula I: 
                         
which is useful as an antiviral agent. The disclosure also provides compounds and processes for the preparation of the compounds that are synthetic intermediates to the compound of formula I.

This application claims priority under 35 U.S.C. §119(e) to U.S.Provisional Application Ser. No. 61/920,446 filed on Dec. 23, 2013, theentirety of which is incorporated herein by reference.

BACKGROUND

The present disclosure relates generally to the field of organicsynthetic methodology for the preparation of Flaviviridae virusinhibitor compounds and their synthetic intermediates.

The hepatitis C virus (HCV), a member of the hepacivirus genera withinthe Flaviviridae family, is the leading cause of chronic liver diseaseworldwide (Boyer, N. et al. J Hepatol. 2000, 32, 98-112). Consequently,a significant focus of current antiviral research is directed toward thedevelopment of improved methods for the treatment of chronic HCVinfections in humans (Ciesek, S., von Hahn T., and Manns, M P., Clin.Liver Dis., 2011, 15, 597-609; Soriano, V. et al, J. Antimicrob.Chemother., 2011, 66, 1573-1686; Brody, H., Nature Outlook, 2011, 474,S1-S7; Gordon, C. P., et al., J. Med. Chem. 2005, 48, 1-20; Maradpour,D., et al., Nat. Rev. Micro. 2007, 5, 453-463).

Virologic cures of patients with chronic HCV infection are difficult toachieve because of the prodigious amount of daily virus production inchronically infected patients and the high spontaneous mutability of HCV(Neumann, et al., Science 1998, 282, 103-7; Fukimoto, et al.,Hepatology, 1996, 24, 1351-4; Domingo, et al., Gene 1985, 40, 1-8;Martell, et al., J. Virol. 1992, 66, 3225-9). HCV treatment is furthercomplicated by the fact that HCV is genetically diverse and expressed asseveral different genotypes and numerous subtypes. For example, HCV iscurrently classified into six major genotypes (designated 1-6), manysubtypes (designated a, b, c, and so on), and about 100 differentstrains (numbered 1, 2, 3, and so on).

HCV is distributed worldwide with genotypes 1, 2, and 3 predominatewithin the United States, Europe, Australia, and East Asia (Japan,Taiwan, Thailand, and China). Genotype 4 is largely found in the MiddleEast, Egypt and central Africa while genotype 5 and 6 are foundpredominantly in South Africa and South East Asia respectively(Simmonds, P. et al. J Virol. 84: 4597-4610, 2010).

There remains a need to develop effective treatments for HCV infections.Suitable compounds for the treatment of HCV infections are disclosed inU.S. Publication No. 2014-0017198, titled “Inhibitors of Hepatitis CVirus” filed on Jul. 2, 2013 including the compound of formula I:

SUMMARY

Presented herewith is an improved process for making a compound offormula I which provides several advantages over known synthesis.Specifically, route I disclosed herein uses a ring closing metathesisstep at a different position than that disclosed previously. This leadsto several advantages over the disclosed synthesis such as higherefficiency and higher overall yield. Further, routes II and III offernew synthetic routes for the compound of formula I.

The present disclosure provides in one embodiment a process for making acompound of formula I, named(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide:

or a co-crystal, or a salt thereof.

In another embodiment, this disclosure provides a process forpreparation of a compound of formula V:

or a co-crystal, or a salt thereof;comprising contacting a compound of formula III or a co-crystal, or asalt thereof, with a compound of formula IV:

under O-arylation conditions to provide the compound of formula V or aco-crystal, or a salt thereof, wherein R is C₁₋₆ alkyl, PG is aprotective group, and R¹ is a leaving group.

In another embodiment, this disclosure provides a process forpreparation of a compound of formula VI:

or a co-crystal, or a salt thereof;comprising subjecting a compound of formula V:

or a co-crystal, or a salt thereof to N-deprotection conditions toprovide the compound of formula VI or a co-crystal, or a salt thereof,wherein R is C₁₋₆ alkyl and PG is a protective group.

In another embodiment, this disclosure provides a process forpreparation of a compound of formula VIII:

or a co-crystal, or a salt thereof;comprising contacting a compound of formula VI:

or a co-crystal, or a salt thereof;with a compound of formula VII:

or a co-crystal, or a salt thereof,under amide coupling conditions to provide the compound of formula VIIIor a co-crystal, or a salt thereof, wherein R is C₁₋₆ alkyl.

In another embodiment, this disclosure provides a process forpreparation of a compound of formula IX:

or a co-crystal, or a salt thereof;comprising performing ring closing metathesis of a compound of formulaVIII:

or a co-crystal, or a salt thereof;to provide the compound of formula IX or a co-crystal, or a saltthereof, wherein R is C₁₋₆ alkyl.

In another embodiment, this disclosure provides a process forpreparation of a compound of formula I, named(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide:

or a co-crystal, or a salt thereof, comprising:a) contacting a compound of formula III or a co-crystal, or a saltthereof, with a compound of formula IV:

under O-arylation conditions to provide a compound of formula V:

or a co-crystal, or a salt thereof;b) subjecting the compound of formula V or a co-crystal, or a saltthereof to N-deprotection conditions to provide a compound of formulaVI:

or a co-crystal, or a salt thereof;c) contacting the compound of formula VI or a co-crystal, or a saltthereof with a compound of formula VII:

or a co-crystal, or a salt thereof,under amide coupling conditions to provide a compound of formula VIII:

or a co-crystal, or a salt thereof;d) performing ring closing metathesis of the compound of formula VIII ora co-crystal, or a salt thereof to provide a compound of formula IX:

or a co-crystal, or a salt thereof;e) hydrogenating the compound of formula IX or a co-crystal, or a saltthereof in presence of a catalyst to provide a compound of formula X:

or a co-crystal, or a salt thereof;f) hydrolyzing the compound of formula X or a co-crystal, or a saltthereof to provide a compound of formula XI:

or a co-crystal, or a salt thereof;g) contacting the compound of formula XI or a co-crystal, or a saltthereof with a compound of formula XII:

or a co-crystal, or a salt thereof;under amide coupling conditions to provide the compound formula I:

or a co-crystal, or a pharmaceutically acceptable salt thereof, whereinR is C₁₋₆ alkyl, PG is a protective group, and R¹ is a leaving group.

In another embodiment, this disclosure provides a process forpreparation of a compound of formula XVIII:

or a co-crystal, or a salt thereof;comprising hydrolyzing a compound of formula VIII:

or a co-crystal, or a salt thereof to provide the compound of formulaXVIII or a co-crystal, or a salt thereof, wherein R is C₁₋₆ alkyl.

In another embodiment, this disclosure provides a process forpreparation of a compound of formula XIX:

or a co-crystal, or a salt thereof;comprising performing ring closing metathesis of the compound of formulaXVIII or a co-crystal, or a salt thereof in presence of a catalyst toprovide the compound of formula XIX.

In another embodiment, this disclosure provides a process forpreparation of a compound of formula XI:

or a co-crystal, or a salt thereof,comprising hydrogenating a compound of formula XIX:

or a co-crystal, or a salt thereof in presence of a catalyst to providea compound of formula XI:

or a co-crystal, or a salt thereof.

In another embodiment, this disclosure provides a process forpreparation of a compound of formula I, named(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide:

or a co-crystal, or a pharmaceutically acceptable salt thereof,comprising:a) contacting a compound of formula III or a co-crystal, or a saltthereof, with a compound of formula IV:

under O-arylation conditions to provide a compound of formula V:

or a co-crystal, or a salt thereof;b) subjecting the compound of formula V or a co-crystal, or a saltthereof to N-deprotection conditions to provide a compound of formulaVI:

or a co-crystal, or a salt thereof;c) contacting the compound of formula VI or a co-crystal, or a saltthereof with a compound of formula VII:

or a co-crystal, or a salt thereof,under amide coupling conditions to provide a compound of formula VIII:

or a co-crystal, or a salt thereof;d) hydrolyzing the compound of formula VIII or a co-crystal, or a saltthereof to provide a compound of formula XVIII:

or a co-crystal, or a salt thereof;e) performing ring closing metathesis of the compound of formula XVIIIor a co-crystal, or a salt thereof in presence of a catalyst to providea compound of formula XIX:

or a co-crystal, or a salt thereof;f) hydrogenating the compound of formula XIX in presence of a catalystto provide a compound of formula XI:

or a co-crystal, or a salt thereof;g) contacting the compound of formula XI or a co-crystal, or a saltthereof with a compound of formula XII:

or a co-crystal, or a salt thereof;under amide coupling conditions to provide the compound formula I:

or a co-crystal, or a salt thereof, wherein R is C₁₋₆ alkyl, PG is aprotective group, and R¹ is a leaving group.

In another embodiment, this disclosure provides a process forpreparation of a compound of formula XV:

or a co-crystal, or a salt thereof, comprising contacting a compound offormula XIII:

or a co-crystal, or a salt thereof,with a compound of formula XIV:

or a co-crystal, or a salt thereof,under cross-metathesis conditions to provide the compound of formula XVor a co-crystal, or a salt thereof, wherein R is C₁₋₆ alkyl and PG is aprotective group.

In another embodiment, this disclosure provides a process forpreparation of a compound of formula XVI:

or a co-crystal, or a salt thereof;comprising hydrogenating the compound of formula XV:

or a co-crystal, or a salt thereof in presence of a catalyst to providethe compound of formula XVI or a co-crystal, or a salt thereof, whereinR is C₁₋₆ alkyl and PG is a protective group.

In another embodiment, this disclosure provides a process forpreparation of a compound of formula XVII:

or a co-crystal, or a salt thereof;comprising subjecting a compound of formula XVI:

or a co-crystal, or a salt thereof;to N-deprotection conditions to provide the compound of formula XVII ora co-crystal, or a salt thereof, wherein R is C₁₋₆ alkyl and PG is aprotective group.

In another embodiment, this disclosure provides a process forpreparation of a compound of formula X:

or a co-crystal, or a salt thereof;comprising contacting the compound of formula XVII with an amidecoupling agent under lactamization conditions to give the compound offormula X or a co-crystal, or a salt thereof, wherein R is C₁₋₆ alkyl.

In another embodiment, this disclosure provides a process forpreparation of a compound of formula I, named(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide:

or a co-crystal, or a salt thereof, comprising:a) contacting a compound of formula XIII:

or a co-crystal, or a salt thereof,with a compound of formula XIV:

or a co-crystal, or a salt thereof,under cross-metathesis conditions to provide a compound of formula XV:

or a co-crystal, or a salt thereof,b) hydrogenating the compound of formula XV or a co-crystal, or a saltthereof in presence of a catalyst to provide a compound of formula XVI:

or a co-crystal, or a salt thereof;c) subjecting the compound of formula XVI or a co-crystal, or a saltthereof to N-deprotection conditions to provide a compound of formulaXVII:

or a co-crystal, or a salt thereof;d) contacting the compound of formula XVII with an amide coupling agentunder lactamization conditions to give a compound of formula X:

or a co-crystal, or a salt thereof;e) hydrolyzing the compound of formula X or a co-crystal, or a saltthereof to provide a compound of formula XI:

or a co-crystal, or a salt thereof; andf) contacting the compound of formula XI or a co-crystal, or a saltthereof with a compound of formula XII:

or a co-crystal, or a salt thereof under amide coupling conditions toprovide the compound formula I:

or a co-crystal, or a salt thereof, wherein R is C₁₋₆ alkyl and PG is aprotective group.

In another embodiment, this disclosure provides a process forpreparation of a compound of formula V-v:

or a co-crystal, or a salt thereof, comprising:a) hydrolyzing the compound of formula A-b:

or a co-crystal, or a salt thereof to provide a compound of formula A-c:

or a co-crystal, or a salt thereof;b) contacting the compound of formula A-c or a co-crystal, or a saltthereof with dicyclohexylamine to provide a compound of formula A-g:

or a co-crystal, or a salt thereof;c) contacting A-g or a co-crystal, or a salt thereof with cinchonidineto provide a compound of formula A-h:

or a co-crystal, or a salt thereof;d) subjecting A-h or a co-crystal, or a salt thereof to Curtiusrearrangement in presence of tert-butanol to provide a compound offormula A-i:

or a co-crystal, or a salt thereof; ande) hydrolysis of A-i or a co-crystal, or a salt thereof to provide V-vor or a co-crystal, or a salt thereof.

In another embodiment, this disclosure provides a compound of formulaIV:

or a co-crystal, or a salt thereof, wherein R¹ is a leaving group.

In another embodiment, this disclosure provides a compound of formula V:

or a co-crystal, or a salt thereof, wherein R is C₁₋₆ alkyl and PG is aprotective group.

In another embodiment, this disclosure provides a compound of formulaVI:

or a co-crystal, or a salt thereof, wherein R is C₁₋₆ alkyl.

In another embodiment, this disclosure provides a compound of formulaVII:

or a co-crystal, or a salt thereof.

In another embodiment, this disclosure provides a compound of formulaVIII:

or a co-crystal, or a salt thereof, wherein R is C₁₋₆ alkyl.

In another embodiment, this disclosure provides a compound of formulaXIII:

or a co-crystal, or a salt thereof.

In another embodiment, this disclosure provides a compound of formulaXIV:

or a co-crystal, or a salt thereof, wherein R is C₁₋₆ alkyl and PG is aprotective group.

In another embodiment, this disclosure provides a compound of formulaXV:

or a co-crystal, or a salt thereof, wherein R is C₁₋₆ alkyl and PG is aprotective group.

In another embodiment, this disclosure provides a compound of formulaXVI:

or a co-crystal, or a salt thereof, wherein R is C₁₋₆ alkyl and PG is aprotective group.

In another embodiment, this disclosure provides a compound of formulaXVII:

or a co-crystal, or a salt thereof, wherein R is C₁₋₆ alkyl.

In another embodiment, this disclosure provides a compound of formulaXVIII:

or a co-crystal, or a salt thereof.

In another embodiment, this disclosure provides a compound of formulaXIX:

or a co-crystal, or a salt thereof.

In another embodiment, this disclosure provides a compound of formulaIV-d:

or a co-crystal, or a salt thereof.

In another embodiment, this disclosure provides a compound of formulaM3:

or a co-crystal, or a salt thereof.

In another embodiment, this disclosure provides a compound of formulaIV-a:

or a co-crystal, or a salt thereof.

In another embodiment, this disclosure provides a compound of formulaIV-b:

or a co-crystal, or a salt thereof.

In another embodiment, this disclosure provides a compound of formulaIV-c:

or a co-crystal, or a salt thereof.

More specific embodiments are described below.

DETAILED DESCRIPTION

Definitions

As used in the present specification, the following words and phrasesare generally intended to have the meanings as set forth below, exceptto the extent that the context in which they are used indicatesotherwise.

The term “alkyl” as used herein refers to a straight or branched chain,saturated hydrocarbon having the indicated number of carbon atoms. Forexample, (C1-C8)alkyl is meant to include, but is not limited to methyl,ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl,isopentyl, neopentyl, hexyl, isohexyl, and neohexyl. In particularembodiments, an alkyl group has 1-20 carbon atoms. An alkyl group can beunsubstituted or optionally substituted with one or more substituents asdescribed herein throughout.

The term “substituted alkyl” refers to:

1) an alkyl group as defined above, having 1, 2, 3, 4 or 5 substituents,(in some embodiments, 1, 2 or 3 substituents) selected from the groupconsisting of alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl,cycloalkoxy, cycloalkenyloxy, acyl, acylamino, acyloxy, amino,substituted amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano,halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio,heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy,heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy,heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,—SO-alkyl, —SO— cycloalkyl, —SO-heterocyclyl, —SO-aryl, —SO-heteroaryl,—SO₂-alkyl, —SO₂-cycloalkyl, —SO₂-heterocyclyl, —SO₂-aryl and—SO₂-heteroaryl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1, 2 or 3substituents chosen from alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl,aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino,cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and —S(O)nR^(a), inwhich R^(a) is alkyl, aryl or heteroaryl and n is 0, 1 or 2; or2) an alkyl group as defined above that is interrupted by 1-10 atoms(e.g. 1, 2, 3, 4 or 5 atoms) independently chosen from oxygen, sulfurand NRa, where Ra is chosen from hydrogen, alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclyl. Allsubstituents may be optionally further substituted by alkyl, alkenyl,alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen,CF₃, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl,heteroaryl, and —S(O)nR^(a), in which R^(a) is alkyl, aryl or heteroaryland n is 0, 1 or 2, or3) an alkyl group as defined above that has both 1, 2, 3, 4 or 5substituents as defined above and is also interrupted by 1-10 atoms(e.g. 1, 2, 3, 4 or 5 atoms) as defined below.

As used herein, the term “interrupted by” means a carbon atom of a group(e.g. an alkyl group) is replaced by a heteroatom.

The term “alkylene” refers to a diradical of a branched or unbranchedsaturated hydrocarbon chain, having from 1 to 20 carbon atoms (e.g. 1-10carbon atoms or 1, 2, 3, 4, 5 or 6 carbon atoms). This term isexemplified by groups such as methylene (—CH₂—), ethylene (—CH₂CH₂—),the propylene isomers (e.g., —CH₂CH₂CH₂— and —CH(CH₃)CH₂—), and thelike.

The term “aralkyl” refers to an aryl group covalently linked to analkylene group, where aryl and alkylene are defined herein. “Optionallysubstituted aralkyl” refers to an optionally substituted aryl groupcovalently linked to an optionally substituted alkylene group. Sucharalkyl groups are exemplified by benzyl, phenylethyl,3-(4-methoxyphenyl)propyl, and the like.

The term “aralkyloxy” refers to the group —O-aralkyl. “Optionallysubstituted aralkyloxy” refers to an optionally substituted aralkylgroup covalently linked to an optionally substituted alkylene group.Such aralkyl groups are exemplified by benzyloxy, phenylethyloxy, andthe like.

The term “alkenyl” refers to a monoradical of a branched or unbranchedunsaturated hydrocarbon group having from 2 to 20 carbon atoms (in someembodiments, from 2 to 10 carbon atoms, e.g. 2 to 6 carbon atoms) andhaving from 1 to 6 carbon-carbon double bonds, e.g. 1, 2 or 3carbon-carbon double bonds. In some embodiments, alkenyl groups includeethenyl (or vinyl, i.e. —CH═CH₂), 1-propylene (or allyl, i.e.—CH₂CH═CH₂), isopropylene (—C(CH₃)═CH₂), and the like.

The term “lower alkenyl” refers to alkenyl as defined above having from2 to 6 carbon atoms.

The term “substituted alkenyl” refers to an alkenyl group as definedabove having 1 to 5 substituents (in some embodiments, 1, 2 or 3substituents) as defined for substituted alkyl.

The term “alkynyl” refers to a monoradical of an unsaturatedhydrocarbon, in some embodiments, having from 2 to 20 carbon atoms (insome embodiments, from 2 to 10 carbon atoms, e.g. 2 to 6 carbon atoms)and having from 1 to 6 carbon-carbon triple bonds e.g. 1, 2 or 3carbon-carbon triple bonds. In some embodiments, alkynyl groups includeethynyl (—C≡CH), propargyl (or propynyl, i.e. —C≡CCH₃), and the like.

The term “substituted alkynyl” refers to an alkynyl group as definedabove having 1 to 5 substituents (in some embodiments, 1, 2 or 3substituents) as defined for substituted alkyl.

The term “hydroxy” or “hydroxyl” refers to a group —OH.

The term “alkoxy” refers to the group —O—R, where R is alkyl or —Y—Z, inwhich Y is alkylene and Z is alkenyl or alkynyl, where alkyl, alkenyland alkynyl are as defined herein. In some embodiments, alkoxy groupsare alkyl-O— and includes, by way of example, methoxy, ethoxy,n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy,n-hexyloxy, 1,2-dimethylbutoxy, and the like.

The term “cycloalkyl” refers to cyclic alkyl groups of from 3 to 20carbon atoms having a single cyclic ring or multiple condensed rings.Such cycloalkyl groups include, by way of example, single ringstructures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl andthe like or multiple ring structures such as adamantanyl andbicyclo[2.2.1]heptanyl or cyclic alkyl groups to which is fused an arylgroup, for example indanyl, and the like, provided that the point ofattachment is through the cyclic alkyl group.

The term “cycloalkenyl” refers to cyclic alkyl groups of from 3 to 20carbon atoms having a single cyclic ring or multiple condensed rings andhaving at least one double bond and in some embodiments, from 1 to 2double bonds.

The terms “substituted cycloalkyl” and “substituted cycloalkenyl” referto cycloalkyl or cycloalkenyl groups having 1, 2, 3, 4 or 5 substituents(in some embodiments, 1, 2 or 3 substituents), selected from the groupconsisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl,cycloalkoxy, cycloalkenyloxy, acyl, acylamino, acyloxy, amino,substituted amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano,halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio,heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy,heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy,heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,—SO-alkyl, —SO-cycloalkyl, —SO-heterocyclyl, —SO-aryl, —SO-heteroaryl,—SO₂-alkyl, —SO₂-cycloalkyl, —SO₂-heterocyclyl, —SO₂-aryl and—SO₂-heteroaryl. The term “substituted cycloalkyl” also includescycloalkyl groups wherein one or more of the annular carbon atoms of thecycloalkyl group has an oxo group bonded thereto. Unless otherwiseconstrained by the definition, all substituents may optionally befurther substituted by 1, 2 or 3 substituents chosen from alkyl,alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy,halogen, CF3, amino, substituted amino, cyano, cycloalkyl, heterocyclyl,aryl, heteroaryl, and —S(O)nR^(a), in which R^(a) is alkyl, aryl orheteroaryl and n is 0, 1 or 2.

The term “cycloalkoxy” refers to the group —O-cycloalkyl

The term “cycloalkenyloxy” refers to the group —O-cycloalkenyl.

The term “aryl” refers to an aromatic carbocyclic group of 6 to 20carbon atoms having a single ring (e.g., phenyl) or multiple rings(e.g., biphenyl) or multiple condensed (fused) rings (e.g., naphthyl,fluorenyl and anthryl). In some embodiments, aryls include phenyl,fluorenyl, naphthyl, anthryl, and the like.

Unless otherwise constrained by the definition for the aryl substituent,such aryl groups can optionally be substituted with 1, 2, 3, 4 or 5substituents (in some embodiments, 1, 2 or 3 substituents), selectedfrom the group consisting of alkyl, alkenyl, alkynyl, alkoxy,cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl, acylamino,acyloxy, amino, substituted amino, aminocarbonyl, alkoxycarbonylamino,azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy,carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol,alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino,heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, —SO-alkyl, —SO-cycloalkyl, —SO-heterocyclyl, —SO-aryl,—SO-heteroaryl, —SO₂-alkyl, —SO₂-cycloalkyl, —SO₂-heterocyclyl,—SO₂-aryl and —SO₂-heteroaryl. Unless otherwise constrained by thedefinition, all substituents may optionally be further substituted by 1,2 or 3 substituents chosen from alkyl, alkenyl, alkynyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino,substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl,and —S(O)nR^(a), in which R^(a) is alkyl, aryl or heteroaryl and n is 0,1 or 2.

The term “aryloxy” refers to the group —O-aryl wherein the aryl group isas defined above, and includes optionally substituted aryl groups asalso defined above. The term “arylthio” refers to the group R—S—, whereR is as defined for aryl.

The term “arylene” herein refers to a diradical of “aryl” as definedabove that is divalent by virtue of formal removal of a hydrogen atomfrom the aryl.

The term “heterocyclyl,” “heterocycle,” or “heterocyclic” refers to amonoradical saturated group having a single ring or multiple condensedrings, having from 1 to 40 carbon atoms and from 1 to 10 hetero atoms(in some embodiments from 1 to 4 heteroatoms), selected from nitrogen,sulfur, phosphorus, and/or oxygen within the ring. In some embodiments,the “heterocyclyl,” “heterocycle,” or “heterocyclic” group is linked tothe remainder of the molecule through one of the heteroatoms within thering.

Unless otherwise constrained by the definition for the heterocyclicsubstituent, such heterocyclic groups can be optionally substituted with1 to 5 substituents (in some embodiments, 1, 2 or 3 substituents),selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy,cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl, acylamino,acyloxy, amino, substituted amino, aminocarbonyl, alkoxycarbonylamino,azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy,carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol,alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino,heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, SO-alkyl, —SO-cycloalkyl, —SO-heterocyclyl, —SO-aryl,—SO-heteroaryl, —SO₂-alkyl, —SO₂-cycloalkyl, —SO₂-heterocyclyl,—SO₂-aryl and —SO₂-heteroaryl. Unless otherwise constrained by thedefinition, all substituents may optionally be further substituted by 1,2 or 3 substituents chosen from alkyl, alkenyl, alkynyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino,substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl,—S(O)nR^(a), in which R^(a) is alkyl, aryl or heteroaryl and n is 0, 1or 2. Examples of heterocyclics include tetrahydrofuranyl, morpholino,piperidinyl, and the like.

The term “heterocyclooxy” refers to the group —O-heterocyclyl.

The term “heteroaryl” refers to a group comprising single or multiplerings comprising 1 to 15 carbon atoms and 1 to 4 heteroatoms selectedfrom oxygen, nitrogen and sulfur within at least one ring. The term“heteroaryl” is generic to the terms “aromatic heteroaryl” and“partially saturated heteroaryl”. The term “aromatic heteroaryl” refersto a heteroaryl in which at least one ring is aromatic, regardless ofthe point of attachment. Examples of aromatic heteroaryls includepyrrole, thiophene, pyridine, quinoline, pteridine. The term “partiallysaturated heteroaryl” refers to a heteroaryl having a structureequivalent to an underlying aromatic heteroaryl which has had one ormore double bonds in an aromatic ring of the underlying aromaticheteroaryl saturated. Examples of partially saturated heteroarylsinclude dihydropyrrole, dihydropyridine, chroman,2-oxo-1,2-dihydropyridin-4-yl, and the like.

Unless otherwise constrained by the definition for the heteroarylsubstituent, such heteroaryl groups can be optionally substituted with 1to 5 substituents (in some embodiments, 1, 2 or 3 substituents) selectedfrom the group consisting alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl,cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl, acylamino, acyloxy,amino, substituted amino, aminocarbonyl, alkoxycarbonylamino, azido,cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl,arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl,aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy,heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,SO-alkyl, —SO-cycloalkyl, —SO-heterocyclyl, —SO-aryl, —SO— heteroaryl,—SO₂-alkyl, —SO₂-cycloalkyl, —SO₂-heterocyclyl, —SO₂-aryl and—SO₂-heteroaryl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1, 2 or 3substituents chosen from alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl,aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino,cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, —S(O)_(n)R^(a), inwhich R^(a) is alkyl, aryl or heteroaryl and n is 0, 1 or 2. Suchheteroaryl groups can have a single ring (e.g., pyridyl or furyl) ormultiple condensed rings (e.g., indolizinyl, benzothiazole orbenzothienyl). Examples of nitrogen heterocyclyls and heteroarylsinclude, but are not limited to, pyrrole, imidazole, pyrazole, pyridine,pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole,indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine,naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine,carbazole, carboline, phenanthridine, acridine, phenanthroline,isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine,imidazolidine, imidazoline, and the like as well as N-alkoxy-nitrogencontaining heteroaryl compounds.

The term “heteroaryloxy” refers to the group —O-heteroaryl.

The term “amino” refers to the group —NH₂.

The term “substituted amino” refers to the group —NRR where each R isindependently selected from the group consisting of hydrogen, alkyl,cycloalkyl, aryl, heteroaryl and heterocyclyl provided that both Rgroups are not hydrogen or a group —Y—Z, in which Y is optionallysubstituted alkylene and Z is alkenyl, cycloalkenyl or alkynyl. Unlessotherwise constrained by the definition, all substituents may optionallybe further substituted by 1, 2 or 3 substituents chosen from alkyl,alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy,halogen, CF₃, amino, substituted amino, cyano, cycloalkyl, heterocyclyl,aryl, heteroaryl, and —S(O)—R^(a), in which R^(a) is alkyl, aryl orheteroaryl and n is 0, 1 or 2.

The term “alkyl amine” refers to R—NH₂ in which R is optionallysubstituted alkyl.

The term “dialkyl amine” refers to R—NHR in which each R isindependently an optionally substituted alkyl.

The term “trialkyl amine” refers to NR₃ in which each R is independentlyan optionally substituted alkyl.

The term “cyano” refers to the group —CN.

The term “azido” refers to a group

The term “keto” or “oxo” refers to a group ═O.

The term “carboxy” refers to a group —C(O)—OH.

The term “ester” or “carboxyester” refers to the group —C(O)OR, where Ris alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, which may beoptionally further substituted by alkyl, alkoxy, halogen, CF3, amino,substituted amino, cyano or, —S(O)nR^(a), in which R^(a) is alkyl, arylor heteroaryl and n is 0, 1 or 2.

The term “acyl” denotes a group —C(O)R, in which R is hydrogen,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted cycloalkenyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl.

The term “carboxyalkyl” refers to the groups —C(O)O-alkyl or—C(O)O-cycloalkyl, where alkyl and cycloalkyl are as defined herein, andmay be optionally further substituted by alkyl, alkenyl, alkynyl,carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃,amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl,heteroaryl, —S(O)nR^(a), in which R^(a) is alkyl, aryl or heteroaryl andn is 0, 1 or 2.

The term “aminocarbonyl” refers to the group —C(O)NRR where each R isindependently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl,heterocyclyl or where both R groups are joined to form a heterocyclicgroup (e.g., morpholino). Unless otherwise constrained by thedefinition, all substituents may optionally be further substituted by 1,2 or 3 substituents chosen from alkyl, alkenyl, alkynyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino,substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl,—S(O)nR^(a), in which R^(a) is alkyl, aryl or heteroaryl and n is 0, 1or 2.

The term “acyloxy” refers to the groups —OC(O)-alkyl, —OC(O)-cycloalkyl,—OC(O)-aryl, —OC(O)-heteroaryl and —OC(O)-heterocyclyl. Unless otherwiseconstrained by the definition, all substituents may optionally befurther substituted by 1, 2 or 3 substituents chosen from alkyl,alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy,halogen, CF3, amino, substituted amino, cyano, cycloalkyl, heterocyclyl,aryl, heteroaryl, —S(O)nR^(a), in which R^(a) is alkyl, aryl orheteroaryl and n is 0, 1 or 2.

The term “acylamino” refers to the group —NRC(O)R where each R isindependently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl orheterocyclyl. All substituents may be optionally further substituted byalkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy,alkoxy, halogen, CF₃, amino, substituted amino, cyano, cycloalkyl,heterocyclyl, aryl, heteroaryl, —S(O)nR^(a), in which R^(a) is alkyl,aryl or heteroaryl and n is 0, 1 or 2.

The term “alkoxycarbonylamino” refers to a group —N(R^(c))C(O)OR inwhich R is optionally substituted alkyl and R^(c) is hydrogen oroptionally substituted alkyl.

The term “aminocarbonylamino” refers to the group —NR^(d)C(O)NRR,wherein R^(d) is hydrogen or optionally substituted alkyl and each R isindependently selected from the group consisting of hydrogen, alkyl,cycloalkyl, aryl, heteroaryl and heterocyclyl. Unless otherwiseconstrained by the definition, all substituents may optionally befurther substituted by 1, 2 or 3 substituents selected from the groupconsisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl,cycloalkoxy, cycloalkenyloxy, acyl, acylamino, acyloxy, amino,substituted amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano,halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio,heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy,heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy,heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,SO-alkyl, —SO-cycloalkyl, —SO-heterocyclyl, —SO-aryl, —SO— heteroaryl,—SO₂-alkyl, —SO₂-cycloalkyl, —SO₂-heterocyclyl, —SO₂-aryl and—SO₂-heteroaryl.

The term “thiol” refers to the group —SH.

The term “thiocarbonyl” refers to a group ═S.

The term “alkylthio” refers to the group —S-alkyl.

The term “substituted alkylthio” refers to the group —S-substitutedalkyl.

The term “heterocyclylthio” refers to the group —S-heterocyclyl.

The term “arylthio” refers to the group —S-aryl.

The term “heteroarylthiol” refers to the group —S-heteroaryl wherein theheteroaryl group is as defined above including optionally substitutedheteroaryl groups as also defined above.

The term “sulfoxide” refers to a group —S(O)R, in which R is alkyl,cycloalkyl, heterocyclyl, aryl or heteroaryl. “Substituted sulfoxide”refers to a group —S(O)R, in which R is substituted alkyl, substitutedcycloalkyl, substituted heterocyclyl, substituted aryl or substitutedheteroaryl, as defined herein.

The term “sulfone” refers to a group —S(O)₂R, in which R is alkyl,cycloalkyl, heterocyclyl, aryl or heteroaryl. “Substituted sulfone”refers to a group —S(O)₂R, in which R is substituted alkyl, substitutedcycloalkyl, substituted heterocyclyl, substituted aryl or substitutedheteroaryl, as defined herein.

The term “aminosulfonyl” refers to the group —S(O)₂NRR, wherein each Ris independently selected from the group consisting of hydrogen, alkyl,cycloalkyl, aryl, heteroaryl and heterocyclyl. Unless otherwiseconstrained by the definition, all substituents may optionally befurther substituted by 1, 2 or 3 substituents selected from the groupconsisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl,cycloalkoxy, cycloalkenyloxy, acyl, acylamino, acyloxy, amino,substituted amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano,halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio,heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy,heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy,heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,SO-alkyl, —SO— cycloalkyl, —SO-heterocyclyl, —SO-aryl, —SO-heteroaryl,—SO₂-alkyl, —SO₂-cycloalkyl, —SO₂-heterocyclyl, —SO₂-aryl and—SO₂-heteroaryl.

The term “hydroxyamino” refers to the group —NHOH.

The term “alkoxyamino” refers to the group —NHOR in which R isoptionally substituted alkyl.

The term “halogen” or “halo” refers to fluoro, bromo, chloro and iodo.

The term “triflate” refers to the trifluoromethanesulfonategroup(—OSO₂—CF₃).

“Optional” or “optionally” means that the subsequently described eventor circumstance may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not.

A “substituted” group includes embodiments in which a monoradicalsubstituent is bound to a single atom of the substituted group (e.g.forming a branch), and also includes embodiments in which thesubstituent may be a diradical bridging group bound to two adjacentatoms of the substituted group, thereby forming a fused ring on thesubstituted group.

Where a given group (moiety) is described herein as being attached to asecond group and the site of attachment is not explicit, the given groupmay be attached at any available site of the given group to anyavailable site of the second group. For example, a “alkyl-substitutedphenyl”, where the attachment sites are not explicit, may have anyavailable site of the alkyl group attached to any available site of thephenyl group. In this regard, an “available site” is a site of the groupat which a hydrogen of the group may be replaced with a substituent.

It is understood that in all substituted groups defined above, polymersarrived at by defining substituents with further substituents tothemselves (e.g., substituted aryl having a substituted aryl group as asubstituent which is itself substituted with a substituted aryl group,etc.) are not intended for inclusion herein. Also not included areinfinite numbers of substituents, whether the substituents are the sameor different. In such cases, the maximum number of such substituents isthree. Each of the above definitions is thus constrained by a limitationthat, for example, substituted aryl groups are limited to -substitutedaryl-(substituted aryl)-substituted aryl.

A compound of a given Formula (e.g. the compound of Formula I) isintended to encompass the compounds of the disclosure, and the salts(e.g. pharmaceutically acceptable salts), esters, isomers, tautomers,solvates, isotopes, hydrates, co-crystals, co-formers and/or prodrugs ofsuch compounds. Additionally, the compounds of the disclosure maypossess one or more asymmetric centers, and can be produced as a racemicmixture or as individual enantiomers or diastereoisomers. The number ofstereoisomers present in any given compound of a given Formula dependsupon the number of asymmetric centers present (there are 2nstereoisomers possible where n is the number of asymmetric centers). Theindividual stereoisomers may be obtained by resolving a racemic ornon-racemic mixture of an intermediate at some appropriate stage of thesynthesis or by resolution of the compound by conventional means. Theindividual stereoisomers (including individual enantiomers anddiastereoisomers) as well as racemic and non-racemic mixtures ofstereoisomers are encompassed within the scope of the presentdisclosure, all of which are intended to be depicted by the structuresof this specification unless otherwise specifically indicated.

“Isomers” are different compounds that have the same molecular formula.Isomers include stereoisomers, enantiomers and diastereomers.

“Stereoisomers” are isomers that contain stereogenic atoms which containthe same connectivity, but which differ only in the way the atoms arearranged in space. The term “stereoisomers” as used herein includes both“enantiomers” and “diastereomers.”

“Enantiomers” are a pair of stereoisomers that are non-superimposablemirror images of each other and do not contain a plane of symmetry. A1:1 mixture of a pair of enantiomers is a “racemic” mixture. The term“(±)” is used to designate a racemic mixture where appropriate.

“Diastereoisomers” are stereoisomers that have at least two stereogenicatoms and may contain a plane of symmetry, but which are notmirror-images of each other in the absence of a plane of symmetry.

The absolute stereochemistry is specified according to the Cahn IngoldPrelog R S system. When the compound is a pure enantiomer thestereochemistry at each chiral carbon may be specified by either R or S.Resolved compounds whose absolute configuration is unknown aredesignated (+) or (−) depending on the direction (dextro- orlaevorotary) that they rotate the plane of polarized light at thewavelength of the sodium D line.

If there is a discrepancy between a depicted structure and a name givento that structure, the depicted structure controls. In addition, if thestereochemistry of a structure or a portion of a structure is notindicated with, for example, bold, wedged, or dashed lines, thestructure or portion of the structure is to be interpreted asencompassing all stereoisomers of it.

The term “solvate” refers to a complex formed by the combining of acompound of Formula I, or any other Formula as disclosed herein, and asolvent. As used herein, the term “solvate” includes a hydrate (i.e., asolvate when the solvent is water).

The term “hydrate” refers to the complex formed by the combining of acompound of Formula I, or any Formula disclosed herein, and water.

The term “co-crystal” refers to a crystalline material formed bycombining a compound of Formula I, or any Formula disclosed herein andone or more co-crystal formers (i.e., a molecule, ion or atom). Incertain instances, co-crystals may have improved properties as comparedto the parent form (i.e., the free molecule, zwitter ion, etc.) or asalt of the parent compound. Improved properties can be increasedsolubility, increased dissolution, increased bioavailability, increaseddose response, decreased hygroscopicity, a crystalline form of anormally amorphous compound, a crystalline form of a difficult to saltor unsaltable compound, decreased form diversity, more desiredmorphology, and the like. Methods for making and characterizingco-crystals are known to those of skill in the art.

The terms “co-former” or “co-crystal former” refer to the non-ionicassociation of a compound of Formula I, or any Formula disclosed hereinwith one or more molecules, ions or atoms. Exemplary co-formers areinorganic or organic bases and/or acids.

Any formula or structure given herein, including Formula I, or anyFormula disclosed herein, is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulas given hereinexcept that one or more atoms are replaced by an atom having a selectedatomic mass or mass number. Examples of isotopes that can beincorporated into compounds of the disclosure include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine,such as, but not limited to ²H (deuterium, D), ³H (tritium), ¹¹C, ¹³C,¹⁴C, ¹⁵N, ¹⁸F, ³¹P, ³²P, ³⁵S, ³⁶Cl and ¹²⁵I. Various isotopicallylabeled compounds of the present disclosure, for example those intowhich radioactive isotopes such as ³H, ¹³C and ¹⁴C are incorporated.Such isotopically labeled compounds may be useful in metabolic studies,reaction kinetic studies, detection or imaging techniques, such aspositron emission tomography (PET) or single-photon emission computedtomography (SPECT) including drug or substrate tissue distributionassays or in radioactive treatment of patients.

The disclosure also included compounds of Formula I, or any Formuladisclosed herein, in which from 1 to “n” hydrogens attached to a carbonatom is/are replaced by deuterium, in which n is the number of hydrogensin the molecule. Such compounds exhibit increased resistance tometabolism and are thus useful for increasing the half life of anycompound of Formula I when administered to a mammal. See, for example,Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism”,Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds aresynthesized by means well known in the art, for example by employingstarting materials in which one or more hydrogen atoms have beenreplaced by deuterium.

Deuterium labeled or substituted therapeutic compounds of the disclosuremay have improved DMPK (drug metabolism and pharmacokinetics)properties, relating to distribution, metabolism and excretion (ADME).Substitution with heavier isotopes such as deuterium may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vivo half-life or reduced dosage requirements. An¹⁸F labeled compound may be useful for PET or SPECT studies.Isotopically labeled compounds of this disclosure and prodrugs thereofcan generally be prepared by carrying out the procedures disclosed inthe schemes or in the examples and preparations described below bysubstituting a readily available isotopically labeled reagent for anon-isotopically labeled reagent. Further, substitution with heavierisotopes, particularly deuterium (i.e., ²H or D) may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vivo half-life or reduced dosage requirements or animprovement in therapeutic index. It is understood that deuterium inthis context is regarded as a substituent in the compound of the FormulaI, or any Formula disclosed herein.

The concentration of such a heavier isotope, specifically deuterium, maybe defined by an isotopic enrichment factor. In the compounds of thisdisclosure any atom not specifically designated as a particular isotopeis meant to represent any stable isotope of that atom. Unless otherwisestated, when a position is designated specifically as “H” or “hydrogen”,the position is understood to have hydrogen at its natural abundanceisotopic composition. Accordingly, in the compounds of this disclosureany atom specifically designated as a deuterium (D) is meant torepresent deuterium.

In many cases, the compounds of this disclosure are capable of formingacid and/or base salts by virtue of the presence of amino and/orcarboxyl groups or groups similar thereto.

Salts of the compounds disclosed herein can be base addition salts oracid addition salts depending on the reactivity of the functional groupspresent on the specific compound. Base addition salts can be derivedfrom inorganic or organic bases. Salts derived from inorganic basesinclude, by way of example only, sodium, potassium, lithium, ammonium,calcium and magnesium salts. Salts derived from organic bases include,but are not limited to, salts of primary, secondary and tertiary amines,such as alkyl amines, dialkyl amines, trialkyl amines, substituted alkylamines, di(substituted alkyl) amines, tri(substituted alkyl) amines,alkenyl amines, dialkenyl amines, trialkenyl amines, substituted alkenylamines, di(substituted alkenyl) amines, tri(substituted alkenyl) amines,cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl) amines,substituted cycloalkyl amines, disubstituted cycloalkyl amine,trisubstituted cycloalkyl amines, cycloalkenyl amines, di(cycloalkenyl)amines, tri(cycloalkenyl) amines, substituted cycloalkenyl amines,disubstituted cycloalkenyl amine, trisubstituted cycloalkenyl amines,aryl amines, diaryl amines, triaryl amines, heteroaryl amines,diheteroaryl amines, triheteroaryl amines, heterocyclic amines,diheterocyclic amines, triheterocyclic amines, mixed di- and tri-amineswhere at least two of the substituents on the amine are different andare selected from the group consisting of alkyl, substituted alkyl,alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic,and the like. Also included are amines where the two or threesubstituents, together with the amino nitrogen, form a heterocyclic orheteroaryl group. Amines are of general structure N(R³⁰)(R³¹)(R³²),wherein mono-substituted amines have 2 of the three substituents onnitrogen (R³⁰, R³¹ and R³²) as hydrogen, di-substituted amines have 1 ofthe three substituents on nitrogen (R³⁰, R³¹ and R³²) as hydrogen,whereas tri-substituted amines have none of the three substituents onnitrogen (R³⁰, R³¹ and R³²) as hydrogen. R³⁰, R³¹ and R³² are selectedfrom a variety of substituents such as hydrogen, optionally substitutedalkyl, aryl, heteroayl, cycloalkyl, cycloalkenyl, heterocyclyl and thelike. The above-mentioned amines refer to the compounds wherein eitherone, two or three substituents on the nitrogen are as listed in thename. For example, the term “cycloalkenyl amine” refers tocycloalkenyl-NH₂, wherein “cycloalkenyl” is as defined herein. The term“diheteroarylamine” refers to NH(heteroaryl)₂, wherein “heteroaryl” isas defined herein and so on.

Specific examples of suitable amines include, by way of example only,isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine,tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, tromethamine,lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline,betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine,purines, piperazine, piperidine, morpholine, N-ethylpiperidine, and thelike.

Acid addition salts can be derived from inorganic or organic acids.Salts derived from inorganic acids include hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and thelike. Salts derived from organic acids include acetic acid, propionicacid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonicacid, succinic acid, maleic acid, fumaric acid, tartaric acid, citricacid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and thelike.

Any of the salts disclosed herein may be optionally pharmaceuticallyacceptable. The term “pharmaceutically acceptable salt” of a givencompound refers to salts that retain the biological effectiveness andproperties of the given compound, and which are not biologically orotherwise undesirable. See: P. Heinrich Stahl and Camille G. Wermuth(Eds.) Pharmaceutical Salts: Properties, Selection, and Use(International Union of Pure and Applied Chemistry), Wiley-VCH; 2ndRevised Edition (May 16, 2011). Pharmaceutically acceptable baseaddition salts can be prepared from inorganic and organic bases.

Pharmaceutically acceptable base addition salts may be salts preparedfrom inorganic and organic bases and pharmaceutically acceptable acidaddition salts may be salts prepared from inorganic and organic acids.

The term “leaving group” refers to an atom or a group of atoms that isdisplaced in a chemical reaction as stable species taking with it thebonding electrons. The non-limiting examples of a leaving group include,halo, methanesulfonyloxy, p-toluenesulfonyloxy,trifluoromethanesulfonyloxy, nonafluorobutanesulfonyloxy,(4-bromo-benzene)sulfonyloxy, (4-nitro-benzene)sulfonyloxy,(2-nitro-benzene)-sulfonyloxy, (4-isopropyl-benzene)sulfonyloxy,(2,4,6-tri-isopropyl-benzene)-sulfonyloxy,(2,4,6-trimethyl-benzene)sulfonyloxy, (4-tert-butyl-benzene)sulfonyloxy,benzenesulfonyloxy, (4-methoxy-benzene)sulfonyloxy, and the like.

The term “O-arylation reaction conditions” refers to the reactionconditions under which an —O—R′ moiety is installed onto a suitablearomatic substrate. The “O-arylation reaction conditions” as disclosedherein typically comprise a base. The non-limiting examples of the baseinclude sodium carbonate (Na₂CO₃) and potassium carbonate (K₂CO₃),potassium-tert-butoxide (KOtBu), lithium-tert-butoxide (LiOtBu),magnesium-tert-butoxide (Mg(OtBu)₂), sodium-tert-butoxide (NaOtBu),sodium hydride (NaH), potassium hexamethyldisilizide (KHMDS), potassiumphosphate (K₃PO₄), potassium hydroxide (KOH), lithium hydroxide (LiOH)as well as organic bases such as 1,4-diazabicyclo[2.2.2]octane (DABCO),1,8-diazabicyclo[5.4. O]undec-7-ene (DBU), and the like.

The term “protective group” refers to a moiety of a compound that masksor alters the properties of a functional group or the properties of thecompound as a whole. The chemical substructure of a protective groupvaries widely. One function of a protective group is to serve as anintermediate in the synthesis of the parental drug substance. Chemicalprotective groups and strategies for protection/deprotection are wellknown in the art. See: “Protective Groups in Organic Chemistry”,Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991. Protectivegroups are often utilized to mask the reactivity of certain functionalgroups, to assist in the efficiency of desired chemical reactions, e.g.,making and breaking chemical bonds in an ordered and planned fashion.Protection of functional groups of a compound alters other physicalproperties besides the reactivity of the protected functional group,such as the polarity, lipophilicity (hydrophobicity), and otherproperties which can be measured by common analytical tools. Chemicallyprotected intermediates may themselves be biologically active orinactive. The non-limiting examples of protective groups for an amineinclude t-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz),9-fluorenylmethoxycarbonyl (Fmoc), and the like.

The term “N-deprotection conditions” refers to the reaction conditionsunder which a protective group from an amine is removed. Thenon-limiting examples of protective groups for an amine includetert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz),9-fluorenylmethoxycarbonyl (Fmoc), and the like. The N-deprotectionconditions for Boc include using an acid such as HCl, methanesulfonicacid, para-toluenesulfonic acid, and the like. The N-deprotectionconditions for Cbz include hydrogenation using hydrogen and a catalystsuch as Pd and the like. The N-deprotection conditions for Fmoc includeusing a base such as 1,8-diazabicyclo[5.4. O]undec-7-ene (DBU),piperidine, and the like.

The term “amide coupling conditions” refers to the reaction conditionsunder which an amine and a carboxylic acid couple to form an amide usinga coupling reagent in presence of a base. The non-limiting examples ofcoupling reagents include 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide(EDC) with hydroxybenzotriazole monohydrate (HOBt),O-(7-Azabenzotriazole-1-yl)-N,N,N,N′-tetramethyluroniumhexafluorophosphate (HATU), 1-hydroxy-7-azabenzotriazole, and the like.The non-limiting examples of the base include N-methylmorpholine,pyridine, morpholine, imidazole, and the like.

The term “ring closing metathesis” refers to the reaction conditionsunder which two alkenes in the same molecule react in presence of acatalyst yielding a cycloalkane and a volatile alkene.

The term “Curtius rearrangement” refers to a reaction in which acarboxylic acid (R—COOH) is converted into an amine (RNH₂) by firstreacting with diphenylphoisphoryl azide to provide an acyl azide(RCON₃), which then rearranges to form an isocyanate (RNCO), which onhydrolysis in presence of an alcohol, for example, tert-butanol,provides a boc-protected amine (R—NHBoc).

The term “cross metathesis conditions” refers to the reaction conditionsunder which two alkenes in separate molecules react in presence of acatalyst yielding a cycloalkane and a volatile alkene.

The non-limiting examples of the catalyst for “ring closing metathesis”and “cross metathesis conditions” include Zhan 1B, Ruthenium-basedGrubbs, Grubbs-Hoveyda, saturated and unsaturated imidazole andphosphine-based catalysts as well as Molybdenum-based catalysts, andvariants thereof. For a representative, non-exhaustive list, see below,wherein Cy is cyclohexyl, Me is methyl, Ph is phenyl, and iPr isisopropyl.

In addition, abbreviations as used herein have respective meanings asfollows:

δ Chemical shift 9-BBN 9-borabicyclo[3.3.1]nonane Ac Acetate Ac₂O Aceticanhydride amu Atomic mass unit aq. aqueous atm Standard atmosphere brbroad Boc t-butyloxycarbonyl Boc₂O di-tert-butyl dicarbonate calc'dcalculated Cbz benzyloxycarbonyl CDI 1,1′-carbonyl-diimidazole CPMECyclopentyl methyl ether d doublet dd doublet of doublets ddd doublet ofdoublet of doublets DCM dichloromethane DIPEA Diiopropylethyl amine DMAcor DMA dimethylacetamide DMAP 4-(dimethylamino)pyridine DMFdimethylformamide DMSO dimethylsulfoxide DPPA diphenylphosphoryl azidedq doublet of quartets dt doublet of triplets EDC1-ethyl-3-(3-dimethylaminopropyl) carbodiimide equiv or eq. equivalentsEt ethyl EtOAc ethyl acetate EtOH ethanol Fmoc9-fluorenylmethoxycarbonyl GCMS gas chromatography mass spectrometry ggrams h hour(s) HATU O-(7-Azabenzotriazole-1-yl)-N,N,N,N′- HOBthydroxybenzotriazole monohydrate HPLC high pressure liquidchromatography HRMS High resolution mass spectrometry Hz hertz iPrIsopropyl IPA Isopropanol or 2-propanol IPAC or IPAc Isopropyl acetate JCoupling constant L liter LCMS liquid chromatography mass spectroscopy MMolar m multiplet Me methyl MeCN acetonitrile MeTHF2-methyltetrahydrofuran MHz megahertz MIBK methylisobutyl ketone mmolmillimole mL milliliter mol mole MP Melting point MS mass spectroscopyMTBE methyl tert-butyl ether m/z Mass to charge N Normal NBSN-bromosuccinimide NCS N-chlorosuccinimide NMM N-methylmorpholine NMPN-methyl-2-pyrrolidinone NMR nuclear magnetic resonance ppm parts permillion psig pounds per square inch rel. relative s singlet T3PPropylphosphonic anhydride t triplet TBAB tetra-n-butyl ammonium bromideTBACl tetra-n-butylammonium chloride TBAI tetra-n-butylammonium iodideTBPB tetra-n-butylphosphonium bromide t-BuOAc tert-butyl acetate TCCAtrichloroisocyanuric acid td Triplet of doublets tdd triplet of doubletof doublets tdt triplet of doublet of triplets THF tetrahydrofuran TsTosyl tt Triplet of triplets tBu or tBu tert-butyl tBuOH t-butanol UPLCultra performance liquid chromatography v/v Volume to volume vol volumewt weight wt/wt Weight to weightProcesses

As described generally above, the disclosure provides in someembodiments processes for making a compound of formula I. In anotherembodiment, the disclosure provides processes for making intermediatesfor the compound of formula I. The processes can also be applied to thesynthesis of a stereoisomer or a mixture of stereoisomers of compound offormula I.

Route I

The present disclosure provides in one embodiment a process for making acompound of formula I, named(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide:

or a stereoisomer, mixture of stereoisomers, a co-crystal, or apharmaceutically acceptable salt thereof.

In another embodiment, this disclosure provides a process forpreparation of a compound of formula I, named(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide:

or a co-crystal, or a salt thereof, comprising:a) contacting a compound of formula III or a co-crystal, or a saltthereof, with a compound of formula IV:

under O-arylation conditions to provide a compound of formula V:

or a co-crystal, or a salt thereof;b) subjecting the compound of formula V or a co-crystal, or a saltthereof to N-deprotection conditions to provide a compound of formulaVI:

or a co-crystal, or a salt thereof;c) contacting the compound of formula VI or a co-crystal, or a saltthereof with a compound of formula VII:

or a co-crystal, or a salt thereof,under amide coupling conditions to provide a compound of formula VIII:

or a co-crystal, or a salt thereof;d) performing ring closing metathesis of the compound of formula VIII ora co-crystal, or a salt thereof to provide a compound of formula IX:

or a co-crystal, or a salt thereof;e) hydrogenating the compound of formula IX or a co-crystal, or a saltthereof in presence of a catalyst to provide a compound of formula X:

or a co-crystal, or a salt thereof;f) hydrolyzing the compound of formula X or a co-crystal, or a saltthereof to provide a compound of formula XI:

or a co-crystal, or a salt thereof;g) contacting the compound of formula XI or a co-crystal, or a saltthereof with a compound of formula XII:

or a co-crystal, or a salt thereof;under amide coupling conditions to provide the compound formula I:

or a co-crystal, or a pharmaceutically acceptable salt thereof, whereinR is C₁₋₆ alkyl, PG is a protective group, and R¹ is a leaving group.

The O-arylation conditions of step a) comprise a base. The non-limitingexamples of the base include sodium carbonate (Na₂CO₃) and potassiumcarbonate (K₂CO₃), potassium-tert-butoxide (KOtBu), cesium carbonate(Cs₂CO₃), lithium-tert-butoxide (LiOtBu), magnesium-tert-butoxide(Mg(OtBu)₂), sodium-tert-butoxide (NaOtBu), sodium hydride (NaH),potassium hexamethyldisilizide (KHMDS), potassium phosphate (K₃PO₄),potassium hydroxide (KOH), lithium hydroxide (LiOH) as well as organicbases such as DABCO, DBU, and the like. In one embodiment, the base iscesium carbonate (Cs₂CO₃).

The non-limiting examples of leaving group include halo,methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy,nonafluorobutanesulfonyloxy, (4-bromo-benzene)sulfonyloxy,(4-nitro-benzene)sulfonyloxy, (2-nitro-benzene)-sulfonyloxy,(4-isopropyl-benzene)sulfonyloxy,(2,4,6-tri-isopropyl-benzene)-sulfonyloxy,(2,4,6-trimethyl-benzene)sulfonyloxy, (4-tertbutyl-benzene)sulfonyloxy,benzenesulfonyloxy, (4-methoxy-benzene)sulfonyloxy.

The O-arylation conditions of step a) further comprise a solvent. Thenon-limiting examples of the solvent include N,N-dimethylformamide(DMF), N-methyl-2-pyrrolidinone (NMP), dimethylsulfoxide (DMSO),acetonitrile (MeCN), acetone; aprotic solvents with small amounts ofadded water (H₂O), ethers such as tetrahydrofuran (THF) and 1,4-dioxane,toluene (in the presence of phase-transfer catalyst), and the like. Inone embodiment, the solvent is N,N-Dimethylacetamide (DMAc). In anotherembodiment, the O-arylation conditions of step a) comprise a temperatureof about 100 to 110° C.

A variety of protective groups, PG, can be used in compound of formulaIII. The non-limiting examples of protective groups for amines includet-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz),9-fluorenylmethoxycarbonyl (Fmoc), and the like. In one embodiment, PGis Boc. The N-deprotection conditions of step b) refer to conditionsunder which the protective group, P, is removed. In one embodiment, PGis Boc and the N-deprotecting conditions comprise an acid such as HCl,methanesulfonic acid, toluenesulfonic acids, and the like. In oneembodiment, the acid is para-toluenesulfonic acid.

The N-deprotection conditions of step b) further comprise a solvent. Thenon-limiting examples of the solvent include methyl tetrahydrofuran,MTBE, dioxane, isopropyl acetate, a combination thereof, and the like.In one embodiment, the solvent is a mixture of methyl tetrahydrofuranand MTBE. In another embodiment, the N-deprotection conditions of stepb) comprise a temperature of about 50 to 55° C.

The amide coupling conditions of step c) comprise a coupling reagent inpresence of a base. The non-limiting examples of coupling reagentsinclude 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) withhydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole,O-(7-azabenzotriazole-1-yl)-N,N,N,N′-tetramethyluroniumhexafluorophosphate (HATU), and the like. The non-limiting examples ofthe base include N-methylmorpholine, pyridine, morpholine,triethylamine, N,N-diisopropylethylamine, imidazole, and the like. Inone embodiment, the coupling conditions of step c) comprise1-ethyl-3-(3-dimethylaminopropyl) carbodiimide and hydroxybenzotriazoleusing N-methylmorpholine. The amide coupling conditions of step c)comprise a solvent. The non-limiting examples of the solvent includedimethylacetamide, acetonitrile, N,N-dimethylformamide, and the like. Inone embodiment, the solvent is N,N-dimethylformamide. In anotherembodiment, the amide coupling conditions of step c) comprise atemperature of about 0 to 20° C.

The ring closing metathesis of step d) comprise a catalyst. Thenon-limiting examples of the catalyst for “ring closing metathesis”include Zhan 1B, ruthenium-based Grubbs, Grubbs-Hoveyda, saturated andunsaturated imidazole and phosphine-based catalysts as well asmolybdenum-based catalysts, and variants thereof. For a representative,non-exhaustive list, see below, wherein Cy is cyclohexyl, Me is methyl,Ph is phenyl, and iPr is isopropyl.

In one embodiment, ring closing metathesis of step d) comprise thecatalyst Zhan 1B.

The ring closing metathesis of step d) further comprise a solvent. Thenon-limiting examples of the solvent include dichloromethane,1,2-dichloroethane, chlorobenzene, hexafluorobenzene, benzene, toluene,THF, methyl-tert-butyl ether, cyclopentyl methyl ether, ethyl acetate,methanol, isopropanol, n-heptane, dimethyl carbonate, dimethylformamide, acetonitrile, and the like. In one embodiment, the solvent istoluene. In another embodiment, the ring closing metathesis of step d)comprise a temperature of about 40 to 110° C. In another embodiment, thetemperature is about 105 to 110° C.

The ring closing metathesis of step d) optionally comprises a promoter.The non-limiting examples of the promoter include acetic acid,benzoquinones, CuI, CsCl, Ti(O-i-Pr)₄, microwave irradiation, ethylene,and the like.

The hydrogenation conditions of step e) comprise hydrogen in presence ofa catalyst. The non-limiting examples of the catalyst include platinum,palladium, ruthenium, nickel, and other metals on carbon, alumina,silica, and other heterogeneous supports; metal nanoparticles;frustrated Lewis pairs such as hydrogen[4-[bis(2,4,6-trimethylphenyl)phosphino]-2,3,5,6-tetrafluorophenyl]hydrobis(2,3,4,5,6-pentafluorophenyl)borate;homogeneous metal catalysts such aschlorotris(triphenylphosphine)rhodium(I) or(1,5-cyclooctadiene)(pyridine)(tricyclohexylphosphine)-iridium(I)hexafluorophosphate, and the like. In one embodiment, the catalyst isplatinum on carbon.

The hydrogenation conditions of step e) further comprise a solvent. Thenon-limiting examples of the solvent include water, protic solvents suchas methanol, ethanol, or acetic acid; aprotic solvents such as dimethylsulfoxide, tetrahydrofuran, ethyl acetate, iso-propyl acetate,acetonitrile, toluene, dichloromethane or acetone; combinations thereof,and the like. In one embodiment, the solvent is iso-propyl acetate. Inanother embodiment, the hydrogenation conditions of step e) comprise atemperature of about 20 to 150° C. In another embodiment, thetemperature is about 20 to 25° C.

The hydrogenation conditions of step e) comprise hydrogen gas orformates such as ammonium formate or formic acid as a source ofhydrogen.

The hydrolysis conditions of step f) comprise either acid hydrolysis orbase hydrolysis. The non-limiting examples of acids for acid hydrolysisinclude protic acids such as sulfuric acid, hydrochloric acid, p-toluenesulfonic acid, or solid-supported acids; Lewis acids such as borontrifluoride, metal salts, metal complexes, or hydrogen-bond donors, andthe like. The non-limiting examples of bases for base hydrolysis includecarbonates such as lithium, sodium, and cesium carbonates, metalhydrides such as sodium hydride, potassium hydride; alkoxides such assodium methoxide, sodium tert-butoxide, lithium tert-butoxide, potassiumtert-butoxide, or tetraalkylammonium alkoxides; hydroxides such assodium hydroxide, potassium hydroxide, tin hydroxides, ortetraalkylammonium hydroxides; amine bases, such as1,8-diazabicycloundec-7-ene, and the like. In one embodiment hydrolysisof step f) comprises a base. In another embodiment, the base is lithiumhydroxide.

The hydrolysis conditions of step f) further comprise a solvent. Thenon-limiting examples of the solvent include polar protic solvents,including water, alcohols such as methanol, ethanol, IPA, tert-butanol,neopentyl alcohols, glycols, and combinations of these with water; polaraprotic solvents, including dimethyl sulfoxide, dimethyl formamide,tetrahydrofuran, 1,4-dioxane, and combinations of these with water;ionic liquids, such as 3-methylimidazolium hexafluorophosphate, and thelike. In one embodiment, the solvent is a mixture of iso-propanol andwater.

The amide coupling conditions of step g) comprise a coupling reagent inpresence of a base and are similar to those described for step c). Inone embodiment, the coupling agent isO-(7-azabenzotriazole-1-yl)-N,N,N,N′-tetramethyluroniumhexafluorophosphate (HATU). In another embodiment the base isN,N-diisipropylethylamine. In another embodiment, the solvent is DMF.

In one embodiment R is C₁₋₆ alkyl. In another embodiment, R is methyl.In another embodiment, R is tert-butyl.

In one embodiment, R¹ is selected from the group consisting halo,methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy,nonafluorobutanesulfonyloxy, (4-bromo-benzene)sulfonyloxy,(4-nitro-benzene)sulfonyloxy, (2-nitro-benzene)-sulfonyloxy,(4-isopropyl-benzene)sulfonyloxy,(2,4,6-tri-isopropyl-benzene)-sulfonyloxy,(2,4,6-trimethyl-benzene)sulfonyloxy, (4-tert-butyl-benzene)sulfonyloxy,benzenesulfonyloxy, (4-methoxy-benzene)sulfonyloxy. In anotherembodiment, R¹ is halo. In another embodiment, R¹ is chloro.

In another embodiment, this disclosure provides a process forpreparation of a compound of formula V:

or a stereoisomer, a mixture of stereoisomers, or a co-crystal, or asalt thereof;comprising contacting a compound of formula III or a co-crystal, or asalt thereof, with a compound of formula IV:

under O-arylation conditions to provide the compound of formula V or aco-crystal, or a salt thereof, wherein R is C₁₋₆ alkyl, PG is aprotective group, and R¹ is a leaving group.

In another embodiment, this disclosure provides a process forpreparation of a compound of formula VI:

or a co-crystal, or a salt thereof;comprising subjecting a compound of formula V:

or a co-crystal, or a salt thereof to N-deprotection conditions toprovide the compound of formula VI or a co-crystal, or a salt thereof,wherein R is C₁₋₆ alkyl and PG is a protective group.

In another embodiment, this disclosure provides a process forpreparation of a compound of formula VIII:

or a co-crystal, or a salt thereof;comprising contacting a compound of formula VI:

or a co-crystal, or a salt thereof;with a compound of formula VII:

or a co-crystal, or a salt thereof,under amide coupling conditions to provide the compound of formula VIIIor a co-crystal, or a salt thereof, wherein R is C₁₋₆ alkyl.

In another embodiment, this disclosure provides a process forpreparation of a compound of formula IX:

or a co-crystal, or a salt thereof;comprising performing ring closing metathesis of a compound of formulaVIII:

or a co-crystal, or a salt thereof;to provide the compound of formula IX or a co-crystal, or a saltthereof, wherein R is C₁₋₆ alkyl.Route II

In another embodiment, this disclosure provides a process forpreparation of a compound of formula I, named(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide:

or a co-crystal, or a pharmaceutically acceptable salt thereof,comprising:a) contacting a compound of formula III or a co-crystal, or a saltthereof, with a compound of formula IV:

under O-arylation conditions to provide a compound of formula V:

or a co-crystal, or a salt thereof;b) subjecting the compound of formula V or a co-crystal, or a saltthereof to N-deprotection conditions to provide a compound of formulaVI:

or a co-crystal, or a salt thereof;c) contacting the compound of formula VI or a co-crystal, or a saltthereof with a compound of formula VII:

or a co-crystal, or a salt thereof,under amide coupling conditions to provide a compound of formula VIII:

or a co-crystal, or a salt thereof;d) hydrolyzing the compound of formula VIII or a co-crystal, or a saltthereof to provide a compound of formula XVIII:

or a co-crystal, or a salt thereof;e) performing ring closing metathesis of the compound of formula XVIIIor a co-crystal, or a salt thereof in presence of a catalyst to providea compound of formula XIX:

or a co-crystal, or a salt thereof;f) hydrogenating the compound of formula XIX in presence of a catalystto provide a compound of formula XI:

or a co-crystal, or a salt thereof;g) contacting the compound of formula XI or a co-crystal, or a saltthereof with a compound of formula XII:

or a co-crystal, or a salt thereof;under amide coupling conditions to provide the compound formula I:

or a co-crystal, or a pharmaceutically acceptable salt thereof, whereinR is C₁₋₆ alkyl, PG is a protective group, and R¹ is a leaving group.

In route II, there is a variation in the order of assembly in that thecompound of formula VIII is first hydrolyzed to provide the compound offormula XVIII which is then subjected to ring closing metathesis to givethe compound of formula XIX which is hydrogenated to give the compoundof formula XI.

In one embodiment R is C₁₋₆ alkyl. In another embodiment, R is methyl.In another embodiment, R is tert-butyl.

In one embodiment, R¹ is selected from the group consisting of halo,methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy,nonafluorobutanesulfonyloxy, (4-bromo-benzene)sulfonyloxy,(4-nitro-benzene)sulfonyloxy, (2-nitro-benzene)-sulfonyloxy,(4-isopropyl-benzene)sulfonyloxy,(2,4,6-tri-isopropyl-benzene)-sulfonyloxy,(2,4,6-trimethyl-benzene)sulfonyloxy, (4-tert-butyl-benzene)sulfonyloxy,benzenesulfonyloxy, (4-methoxy-benzene)sulfonyloxy. In anotherembodiment, R¹ is halo. In another embodiment, R¹ is chloro.

In another embodiment, this disclosure provides a process forpreparation of a compound of formula XVIII:

or a co-crystal, or a salt thereof;comprising hydrolyzing a compound of formula VIII:

or a co-crystal, or a salt thereof to provide the compound of formulaXVIII or a co-crystal, or a salt thereof, wherein R is C₁₋₆ alkyl.

In another embodiment, this disclosure provides a process forpreparation of a compound of formula XIX:

or a co-crystal, or a salt thereof;comprising performing ring closing metathesis of the compound of formulaXVIII or a co-crystal, or a salt thereof in presence of a catalyst toprovide the compound of formula XIX.

In another embodiment, this disclosure provides a process forpreparation of a compound of formula XI:

or a co-crystal, or a salt thereof,comprising hydrogenating a compound of formula XIX:

or a co-crystal, or a salt thereof in presence of a catalyst to providethe compound of formula XI or a co-crystal, or a salt thereof.Route III

In another embodiment, this disclosure provides a process forpreparation of a compound of formula I, named(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide:

or a co-crystal, or a pharmaceutically acceptable salt thereof,comprising:a) contacting a compound of formula XIII:

or a co-crystal, or a salt thereof,with a compound of formula XIV:

or a co-crystal, or a salt thereof,under cross-metathesis conditions to provide a compound of formula XV:

or a co-crystal, or a salt thereof,b) hydrogenating the compound of formula XV or a co-crystal, or a saltthereof in presence of a catalyst to provide a compound of formula XVI:

or a co-crystal, or a salt thereof;c) subjecting the compound of formula XVI or a co-crystal, or a saltthereof to N-deprotection conditions to provide a compound of formulaXVII:

or a co-crystal, or a salt thereof;d) contacting the compound of formula XVII with an amide coupling agentunder lactamization conditions to give a compound of formula X:

or a co-crystal, or a salt thereof;e) hydrolyzing the compound of formula X or a co-crystal, or a saltthereof to provide a compound of formula XI:

or a co-crystal, or a salt thereof; andf) contacting the compound of formula XI or a co-crystal, or a saltthereof with a compound of formula XII:

or a co-crystal, or a salt thereof under amide coupling conditions toprovide the compound formula I:

or a co-crystal, or a pharmaceutically acceptable salt thereof, whereinR is C₁₋₆ alkyl and PG is a protective group.

The cross-metathesis conditions comprise a catalyst and a solvent. Inone embodiment, the catalyst is Zhan B. In another embodiment, thesolvent is toluene. In another embodiment, the cross-metathesisconditions comprise a temperature of about 90-100° C.

The hydrogenation conditions of step b) comprise a catalyst and asolvent. In one embodiment, the catalyst is platinum on carbon. Inanother embodiment, the solvent is isopropyl acetate.

The N-deprotection conditions for step c) comprise an acid and asolvent. In one embodiment, PG is Boc. In another embodiment, the acidis HCl. In another embodiment, the solvent is dioxane.

The lactamization conditions of step d) comprise a coupling reagent inpresence of a base and a solvent. In one embodiment, the coupling agentis 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) withhydroxybenzotriazole monohydrate (HOBt). In another embodiment, the baseis triethylamine. In another embodiment, the solvent isN,N-dimethylformamide (DMF).

In one embodiment R is C₁₋₆ alkyl. In another embodiment, R is methyl.In another embodiment, R is tert-butyl.

In another embodiment, this disclosure provides a process forpreparation of a compound of formula XV:

or a co-crystal, or a salt thereof, comprising contacting a compound offormula XIII:

or a co-crystal, or a salt thereof,with a compound of formula XIV:

or a co-crystal, or a salt thereof,under cross-metathesis conditions to provide the compound of formula XVor a co-crystal, or a salt thereof, wherein R is C₁₋₆ alkyl and PG is aprotective group.

In another embodiment, this disclosure provides a process forpreparation of a compound of formula XVI:

or a co-crystal, or a salt thereof;comprising hydrogenating the compound of formula XV:

or a co-crystal, or a salt thereof in presence of a catalyst to providethe compound of formula XVI or a co-crystal, or a salt thereof, whereinR is C₁₋₆ alkyl and PG is a protective group.

In another embodiment, this disclosure provides a process forpreparation of a compound of formula XVII:

or a co-crystal, or a salt thereof;comprising subjecting a compound of formula XVI:

or a co-crystal, or a salt thereof;to N-deprotection conditions to provide the compound of formula XVII ora co-crystal, or a salt thereof, wherein R is C₁₋₆ alkyl and PG is aprotective group.

In another embodiment, this disclosure provides a process forpreparation of a compound of formula X:

or a co-crystal, or a salt thereof;comprising contacting the compound of formula XVII with an amidecoupling agent under lactamization conditions to give the compound offormula X or a co-crystal, or a salt thereof, wherein R is C₁₋₆ alkyl.Compounds

In another embodiment, this disclosure provides a compound of formulaIV:

or a co-crystal, or a salt thereof, wherein R¹ is a leaving group. Inone embodiment, R¹ is selected from the group consisting of halo,—O-(toluenesulfonyl), —O-(trifluoromethanesulfonyl), —O-(4-nitrophenyl),and —B(OY)₂, wherein each Y is independently H or C₁₋₄ alkyl, or two Ygroups together with the atoms to which they are attached form a 5- to6-membered ring. In another embodiment, R¹ is halo. In anotherembodiment, R¹ is chloro.

In another embodiment, R¹ is NH₂.

In another embodiment, this disclosure provides a compound of formula V:

or a co-crystal, or a salt thereof, wherein R is C₁₋₆ alkyl and PG is aprotective group. In one embodiment, PG is selected from the groupconsisting of Boc, Cbz, and Fmoc. In another embodiment, PG is Boc. Inanother embodiment, R is methyl. In another embodiment, R is tert-butyl.

In another embodiment, this disclosure provides a compound of formulaVI:

or a co-crystal, or a salt thereof, wherein R is C₁₋₆ alkyl. In anotherembodiment, R is methyl. In another embodiment, R is tert-butyl.

In another embodiment, this disclosure provides a compound of formulaVII:

or a co-crystal, or a salt thereof.

In another embodiment, this disclosure provides a compound of formulaVIII:

or a co-crystal, or a salt thereof, wherein R is C₁₋₆ alkyl. In anotherembodiment, R is methyl. In another embodiment, R is tert-butyl.

In another embodiment, this disclosure provides a compound of formulaXIII:

or a co-crystal, or a salt thereof.

In another embodiment, this disclosure provides a compound of formulaXIV:

or a co-crystal, or a salt thereof, wherein R is C₁₋₆ alkyl and PG is aprotective group. In one embodiment, PG is selected from the groupconsisting of Boc, Cbz, and Fmoc. In another embodiment, PG is Boc. Inanother embodiment, R is methyl. In another embodiment, R is tert-butyl.

In another embodiment, this disclosure provides a compound of formulaXV:

or a co-crystal, or a salt thereof, wherein R is C₁₋₆ alkyl and PG is aprotective group. In one embodiment, PG is selected from the groupconsisting of Boc, Cbz, and Fmoc. In another embodiment, PG is Boc. Inanother embodiment, R is methyl. In another embodiment, R is tert-butyl.

In another embodiment, this disclosure provides a compound of formulaXVI:

or a co-crystal, or a salt thereof, wherein R is C₁₋₆ alkyl and PG is aprotective group. In one embodiment, PG is selected from the groupconsisting of Boc, Cbz, and Fmoc. In another embodiment, PG is Boc. Inanother embodiment, R is methyl. In another embodiment, R is tert-butyl.

In another embodiment, this disclosure provides a compound of formulaXVII:

or a co-crystal, or a salt thereof, wherein R is C₁₋₆ alkyl. In oneembodiment, R is methyl. In another embodiment, R is tert-butyl.

In another embodiment, this disclosure provides a compound of formulaXVIII:

or a co-crystal, or a salt thereof.

In another embodiment, this disclosure provides a compound of formulaXIX:

or a co-crystal, or a salt thereof.

The intermediates in the process for the synthesis of formula I can beused in the next step with or without purification. The conventionalmeans of purification include recrystallization, chromatography (e.g.adsorbent, ion exchange, and HPLC), and the like.

In some embodiments, the means of purification can include chiralresolution of one or more intermediates in the process for the synthesisof formula I and/or formula I. Non-limiting examples of such methodsinclude, crystallization, a chiral resolving agent, and/or chiralchromatography. For example, in some embodiments, compounds of formula Ican be further purified via crystallization with cinchonine alkaloids.

EXAMPLES

The compounds of the disclosure may be prepared using methods disclosedherein and routine modifications thereof which will be apparent giventhe disclosure herein and methods well known in the art. Conventionaland well-known synthetic methods may be used in addition to theteachings herein. The synthesis of compounds described herein, may beaccomplished as described in the following examples. If available,reagents may be purchased commercially, e.g. from Sigma Aldrich or otherchemical suppliers. Unless otherwise noted, the starting materials forthe following reactions may be obtained from commercial sources.

Example 1 Synthesis of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide(I) by route I

Compound of formula I was synthesized via route I as shown below:

Synthesis of Intermediates for Compound of Formula I A. Synthesis ofMethyl(2S,3S,4R)-3-ethyl-4-hydroxypyrrolidine-2-carboxylate TosylateSalt (II)

The order of reduction of the double bond and ketone was reversed so newintermediates were formed, B (R=tert-butyl) and C (R=tert-butyl). Thetert-butyl ester was used to make D in U.S. Publication No.2014-0017198; however, it was converted directly to the methyl estertosylate salt without chromatography and crystallized to removediastereomeric impurities. A single crystal X-Ray of the tosylate saltII was obtained.

Step 1: Synthesis of A

I. Enamine Formation to A

DMF-DMA (125.3 g, 2.0 eq.) and DCM (300 mL) were combined in a reactionvessel and heated to 45° C. In a separate container the commerciallyavailable di-tert-butyl(S)-4-oxopyrrolidine-1,2-dicarboxylate (150 g)was dissolved in DCM (300 mL) under N₂. This solution was charged overabout 3 hours to the reaction vessel containing the DMF-DMA solution.Upon reaction completion, the solution was cooled to about roomtemperature. 5% LiCl (750 mL) was added to the reactor and the mixturewas stirred. The layers were separated and the aqueous layer wasremoved. The organic layer was washed with water (750 mL) and dried withNa₂SO₄ and the mixture was filtered.

The filtrate was concentrated to ˜200 mL and heptane (600 mL) wascharged to obtain a murky solution. The mixture was further concentratedto remove residual DCM. Additional heptane (600 mL) was added and themixture was heated to about 50 to 60° C. and aged for about 1 h toobtain a slurry. The slurry was cooled to about 15° C. over about 4hours before aging at about 15° C. overnight (˜18 h). Intermediate A(R=tert-butyl) was isolated via vacuum filtration and rinsed with 2×heptane. The resulting solid was dried at about 45° C. to obtain A(R=tert-butyl). ¹H NMR (400 MHz, CDCl₃) (mixture of E/Z isomer): δ 7.4(s, 1H), 5.2-5.3 (s, 1H), 3.8 (d, 2H) 3.2 (broad s, 6H), 1.5 (s, 9H),1.4 (s, 9H). UPLC/MS M+1=341 amu.

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, alternative solvents may be used,such as other polar aprotic solvents (e.g. dimethylformamide, methylt-butyl ether, and isopropyl acetate) or nonpolar solvents (e.g.toluene, cyclohexane, heptane) may be used. The reaction could also beperformed without solvent or a mixture of the aforementioned solvents.Further, temperatures ranging from about 25 to about 50° C. mayemployed. Alternative crystallization solvent systems (e.g. DCM:heptane,Toluene:heptane, cyclohexane:heptane, and cyclohexane) may also be used.

Step 2: Synthesis of B (R=tert-butyl)

I. Methylation of A (R=tert-butyl) to B (R=tert-butyl):

To a reaction vessel was added A (151 g, 0.44 mol, 1.0 equiv). Thevessel was evacuated, purged with nitrogen, and the substrate wasdissolved in MeTHF (450 mL, 3 vol). The reaction mixture was cooled toan internal temperature of about −12° C. and treated dropwise withmethylmagnesium bromide (155 mL of a 3.0 M solution in diethyl ether,0.55 mol, 1.25 equiv) over about 1 h. Upon reaction completion (about 2h), a reverse quench was performed by adding the reaction to coldsaturated aqueous ammonium chloride (400 mL). If an emulsion wasobserved, more aqueous ammonium chloride or 2 M HCl was added. Theaqueous layer was extracted with toluene (1×200 mL). The organic layerswere combined, washed with 1 M HCl (150 mL), then brine (150 mL), andconcentrated in vacuo to provide B. ¹H NMR (400 MHz, CDCl₃): δ 6.90-6.92(1H, m), 5.08-5.16 (1H, m), 3.94-4.00 (2H, m), 2.02-2.04 (3H, m),1.44-1.49 (18H, m).

Alternative reagents and reactions conditions to those disclosed abovemay also be employed. For example, other nucleophiles, such as methylmagnesium reagents, methyl lithium, methyl lithium-lithium chloride,methyl cuprates, and other methyl metal reagents may be employed. Inaddition, alternative solvents may also be used, such as other polar ornonpolar aprotic solvents.

Step 3: Synthesis of C (R=tert-butyl)

I. Hydrogenation of B (R=tert-butyl) to C (R=tert-butyl):

Enone B (R=tert-butyl) (32.0 g, 0.10 mol) was dissolved in toluene (3vol) under an atmosphere of N₂. Pd/C was subsequently added (1.1 g, 0.5mol %) and the reaction was flushed with N₂, followed by H₂, and stirredvigorously at room temperature under 1 atm of H₂. After completion ofthe reaction, diatomaceous earth (0.1 S, 13.2 g) was added and themixture was stirred for 5 minutes. The heterogeneous mixture wasfiltered through diatomaceous earth and rinsed with additional toluene(0.5-1 vol) and concentrated to dryness to provide C. ¹H NMR (400 MHz,CD₃OD): δ 4.68 (dd, J=36.9, 9.3 Hz, 1H), 3.99-3.75 (m, 2H), 2.63 (tdd,J=13.7, 9.2, 4.6 Hz, 1H), 1.89 (dt, J=13.8, 6.7 Hz, 1H), 1.46 (s, 9H),1.43 (s, 9H), 1.30-1.16 (m, 1H), 1.07 (t, J=7.4 Hz, 3H).

Alternative reagents and reactions conditions to those disclosed abovemay also be employed. For example, other heterogeneous metal catalysts,such as platinum, palladium, ruthenium, nickel, and other metals oncarbon, alumina, silica, and other heterogeneous supports, or metalnanoparticles may be used. In addition, Lewis pairs such as hydrogen[4-[bis(2,4,6-trimethylphenyl)phosphino]-2,3,5,6-tetrafluorophenyl]hydrobis(2,3,4,5,6-pentafluorophenyl)borateor homogeneous metal catalysts such aschlorotris(triphenylphosphine)rhodium(I) or(1,5-cyclooctadiene)(pyridine)(tricyclohexylphosphine)-iridium(I)hexafluorophosphate may also be employed. Other solvents (e.g., water,protic solvents such as methanol, ethanol, or acetic acid), aproticsolvents (e.g., dimethyl sulfoxide, tetrahydrofuran, ethyl acetate,acetonitrile, toluene, dichloromethane or acetone) or combinations ofthe above may be used. Further, temperatures can range from about −20°C. to about 150° C. In addition, alternative hydrogen gas at a range ofpressures can be used or formates such as ammonium formate or formicacid can be employed. Alternatively, diimide reduction conditions may beemployed.

Step 4: Synthesis of D (R=tert-butyl)

I. Reduction of C (R=tert-butyl) to provide D (R=tert-butyl)

ZnCl₂ (27.3 g, 200 mmol, 2 equiv) and CPME (7 vol relative to C, 220 mL)were combined and the heterogeneous mixture was warmed to an internaltemperature of about 95° C. and stirred for about 1.5 hours at thattemperature. The resulting slurry was cooled to about 25° C. NaBH₄ (7.56g, 200 mmol, 2 equiv) was added and the mixture was stirred overnight(˜18 hrs).

The slurry was cooled to about 0° C., and the solution of C(R=tert-butyl) (˜100 mmol) in toluene (3 total vol) was added slowlywhile maintaining the temperature to about below +3° C. After addition,the mixture was stirred at about 0° C. until complete consumption of thestarting material. The reaction was quenched by reverse addition into asolution of citric acid (2.5 equiv, 48 g) in ice water (200 mL). Thelayers were separated and the organic layer was washed with brine (60mL, 2 vol), dried over MgSO₄ (0.05 S, 1.5 g), and filtered. The crudeorganic solution was concentrated, diluted with 2 volumes of hexanes andfiltered through silica gel, eluting with 1:1 acetone:hexanes.Concentration in vacuo provided compound of formula D (R=tert-butyl).

¹H NMR (400 MHz, CDCl₃): δ 4.30 (dd, J=26.4, 8.4 Hz, 1H), 4.24-4.14 (m,1H), 3.89 (ddd, J=14.6, 10.6, 7.5 Hz, 1H), 3.15 (ddd, J=17.7, 10.6, 7.1Hz, 1H), 2.20-2.05 (m, 2H), 1.70-1.59 (m, 1H), 1.48 (s, 9H), 1.44 (s,9H), 1.35-1.23 (m, 1H), 1.07 (t, J=7.4 Hz, 3H).

Alternative reagents and reactions conditions to those disclosed abovemay also be employed. For example, other reducing regents may beemployed, such as borohydrides (e.g., sodium, lithium, or calciumborohyride), boroacyloxyhydrides (e.g., sodium acetoxyborohyride, orlithium trifluoroacetoxyborohydride), borane, or complexes of borane,hydrogen, aluminum hydride reagents (e.g., lithium aluminum hydride ordi-isobutylaluminum hydride), diborane, diazene, sodiumcyanoborohydride, 9-BBN, tributyltin hydride, silanes (e.g.,triethylsilane), aluminumisopropylates in combination with isopropanol.Further, alternative catalysts or promoters may be employed, such asLewis or Bronsted acids, or combinations of the two; bases;heterogeneous metal catalysts (e.g., platinum, palladium, ruthenium,nickel, and other metals on carbon, alumina, silica, and otherheterogeneous supports); metal nanoparticles; frustrated Lewis pairs(e.g., hydrogen[4-[bis(2,4,6-trimethylphenyl)phosphino]-2,3,5,6-tetrafluorophenyl]hydrobis(2,3,4,5,6-pentafluorophenyl)borate);homogeneous metal catalysts (e.g., such aschlorotris(triphenylphosphine)rhodium(I) or(1,5-Cyclooctadiene)(pyridine)(tricyclohexylphosphine)-iridium(I)hexafluorophosphate). In addition, other solvents such as water, proticsolvents (e.g., methanol, ethanol, or acetic acid), aprotic solvents(e.g., dimethyl sulfoxide, tetrahydrofuran, ethyl acetate, acetonitrile,toluene, dichloromethane or acetone), combinations of the above may beemployed.

Synthesis of Compound of Formula II (R═CH₃)

Deprotection and Transesterification of D (R=tert-butyl) to II (R═CH₃):

D (R=tBu) (5.55 g, 17.6 mmol) and methanol (55.5 mL) were combined in areaction vessel. p-Toluenesulfonic acid (10.7 g, 3.2 eq.) was charged tothe solution and the mixture is stirred for about 1 hour at roomtemperature. The mixture was then heated to about 60° C. The reactionwas stirred until reaction completion. The reaction mixture wasconcentrated to about 4 volumes and cooled to about 45° C. MTBE (4volumes) were added slowly followed by II seed (0.05%). The mixture wasthen aged for about 30 minutes. Additional MTBE (5 volumes) were chargedover about 90 minutes and the resulting mixture was stirred overnight.

The mixture was filtered and rinsed with 2 volumes of MTBE. Theresulting wet cake was dried under vacuum at about 40° C. to obtaincompound II (R═CH₃) as a tosylate salt. ¹H NMR (400 MHz, MeOD) δ 7.7 (d,2H), 7.2 (d, 2H), 4.7 (d, 1H), 4.3 (m, 1H), 3.8 (s, 3H), 3.6 (m, 1H),3.2 (m, 1H), 2.4 (m, 1H), 2.3 (s, 3H), 1.3 (m, 2H), 1.0 (t, 3H). LC/MSM+1=174.1

Alternative reagents and reactions conditions to those disclosed abovemay also be employed. For example, methanol with co-solvents, MTBE,toluene or other non-alcoholic solvents may be used and temperaturesranging from about 0 to 60° C. may be employed. In addition, alternativecrystallization solvent systems may include methanol:MTBE; ethanol:MTBE;or acetone:MTBE. Further, alternative salts (e.g., HCl, HBr, mesylate,brosylate, triflate, benzenesulfonate) may be employed.

B. Synthesis of3-Chloro-2-(1,1-difluorobut-3-en-1-yl)-6-methoxyquinoxaline (IV)

Compound IV was synthesized via two different routes as discussed below.

Compound IV contains one more methylene group than the analog used inU.S. Publication No. 2014-0017198 and so requires a different startingmaterial. Ethyl trifluoropyruvate was converted to intermediate G inthree steps. Intermediate G was telescoped through to a 4:1regioisomeric mixture of J and K. In the U.S. Publication No.2014-0017198, a nitro, amino-anisole was used for the ring formation ina two-step process of reacting the amine first and then reducing thenitro group to allow cyclization. Two regioisomers were formed. In thisroute, the starting material was instead the diamino analog and similarmixture was obtained. The mixture was chlorinated and the desired isomerIV was purified by conventional methods.

Step 1: Synthesis of G

I. Synthesis of Intermediate of Formula G from Ethyl Trifluoropyruvate:

a. Allylation of Ethyl Trifluoropyruvate to Provide E:

To a reaction vessel was charged ethyl trifluoropyruvate (86 g, 0.5056mol, 1.0 equivalent) and dichloromethane (260 mL). Allyl alcohol (31 g,0.5337 mol, 1.1 equivalent) was added dropwise over about 30 minuteswhile maintaining the reaction temperature less than about 27° C. Thereaction was cooled to about 5° C. and pyridine (123 mL, 1.52 mol, 3.0equivalents) was added over about 50 minutes, maintaining a reactiontemperature below about 8° C., followed by charging thionyl chloride (90g, 0.76 mol, 1.5 equivalents) over about 90 minutes while maintainingthe reaction temperature below about 12° C. The reaction was stirred forabout 30 minutes at 5 to 10° C., warmed to about 22° C. over about 30minutes and held at about 22° C. until the reaction was deemed complete.The reaction mixture was poured into 860 mL of chilled (about 8° C.)water and the phases separated. The aqueous phase was back-extractedwith 200 mL dichloromethane. The combined dichloromethane phases werewashed successively with water (860 mL), 5 wt % NaHCO₃ solution (2×250mL), and a final water wash (250 mL) and dried over Na₂SO₄. After theremoval of the solvents, the crude product E was isolated and useddirectly for the next step. ¹H NMR (300 MHz, CDCl₃): δ 5.92 (m, 1H),5.38 (dq, J=14.1, 1.4 Hz, 1H), 5.27 (dq, J=10.3, 1.2 Hz, 1H), 4.40 (d,J=7.1 Hz, 2H), 4.34 (m, 2H), 1.30 (t, J=7.1 Hz, 3H).

II. Zn-Mediated Elimination of ClF from E to Provide F Followed byClaisen to Provide G:

To a reaction vessel was charged zinc powder (324 g, 4.95 mol, 2.0equivalents), CuI (6 g, 0.032 mmol, 0.013 equivalents) andN,N-dimethylformamide (DMF) (3.0 L). The mixture was stirred vigorouslyas Me₃SiCl (309 mL, 2.43 mmol, 1.0 equivalents) was charged dropwise viaaddition funnel over about 10 minutes, maintaining the reactiontemperature at about <25° C. The reaction was stirred for about 30minutes at about 25° C. The reaction was then cooled to 0 to 5° C. over20 minutes and a solution of compound E (600 g, 2.43 mol, 1.0equivalents) in DMF (3.0 L) was added slowly over about 60 minutes,maintaining the reaction temperature about <10° C. The reaction wasstirred for about 30 minutes at 5 to 10° C., warmed to about 22° C. overabout 30 minutes and then held at about 22° C. until the reaction wasdeemed complete by ¹⁹F NMR (typically 1-2 hours).

III. Claisen Rearrangement of F to Provide G

The above reaction mixture was filtered and washed with ethyl acetate(2×3 L). Water (1.5 L) was added to the organic phase and the layerswere separated. The organic layer was washed two additional portions ofwater (2×1.5 L). The organic solution was concentrated to obtain crudeF. This was dissolved in 3.0 L (5 volumes) of toluene and heated toabout 80° C. until the reaction was deemed complete (typically 1-3 h).The reaction was cooled to about 22° C. and the solvent removed viarotary evaporation to obtain the crude product G (˜70 wt %)). ¹H NMR(300 MHz, CDCl₃): δ 5.90 (m, 1H), 5.28 (m, 2H), 4.40 (q, J=7.1 Hz, 2H),2.83 (dt, J=18.5, 7.0 Hz, 2H), 1.32 (t, J=7.0 Hz, 3H); ¹⁹F NMR (CDCl₃) δ−112.8 (t).

Alternative reagents and reactions conditions to those disclosed abovemay also be employed. For example, other amine bases (e.g.,4-dimethylaminopyridine, imidazole, or triethylamine) may be used. Inaddition, alternate allylating agent (e.g., allyl chloride, allylbromide), halogenating agent (e.g., thionyl bromide), olefinating agent(e.g., magnesium), or zinc activator (e.g., methanesulfonic acid,hydrochloric acid, di-isobutylaluminum hydride, diethylaluminumchloride) may be employed. Further, other solvents (e.g.,dichloromethane, benzene, toluene, methyl-t-butyl ether,tetrahydrofuran, or 2-methyl tetrahydrofuran) can be used.

Step 2: Synthesis of H

I. Synthesis of H from G

To a reaction flask was charged G (26.2 g, 136.6 mmol, 1.0 equivalent)and THF (236 mL, 9 vol.). Water (52 mL, 2 vol.) was charged followed byLiOH.H₂O (14.9 g, 354.5 mmol, 2.6 equiv.) maintaining a reactiontemperature below about 33° C. The reaction was held at about 22° C. forabout 3 hours followed by quenching with 250 mL of 1M HCl. The pH wasthen adjusted to 3 by addition of concentrated HCl (20 mL). The phaseswere separated and the aqueous phase was back-extracted withmethyl-t-butyl ether (260 mL). The layers were split and NaCl (52 grams)was added to the aqueous phase which was extracted with MTBE (2×130 mL)followed by EtOAc (50 mL). All the organic phases were combined anddried over Na₂SO₄, filtered, concentrated and dried under vacuum toobtain H. ¹H-NMR (400 MHz, DMSO-d₆) δ 13.2 (br s, 1H), 6.92 (br s, 2H),5.83-5.70 (m, 1H), 5.20-5.13 (m, 2H), 2.83-2.65 (m, 2H). ¹⁹F-NMR(DMSO-d₆) δ −88.20 (t, J=20.8 Hz).

Alternative reagents and reactions conditions to those disclosed abovemay also be employed. For example, other bases may be used, such aspotassium/sodium hydroxide, potassium-tert-butoxide, or sodium/potassiumtrimethylsiloxide. In addition, alternate catalysts (e.g.tetrabutylammonium chloride) may be employed. Further, other solventsmay be used, such as methyl-t-butyl ether/water, 2-methyltetrahydrofuran/water, tetrahydrofuran/water, methyl-t-butylether/water/heptane.

Step 3: Synthesis of J

I. Condensation Followed by Cyclization to Provide J from H:

To a reaction vessel was charged diamine (6.06 g, 28.7 mmol, 1.0equivalent) and ethanol (130 mL). Triethylamine (8.8 mL, 63.1 mol, 2.2equivalents) was charged over about 5 minutes maintaining the reactiontemperature about <25° C. The reaction was agitated for about 10 minutesto afford a solution. Acetic acid (16.4 mL, 287 mmol, 10 equiv.)followed by a solution of H (5.75 g, 31.6 mmol, 1.1 equiv.) in ethanol(40 mL) was charged and the reaction was held at about 22° C. until thereaction was complete. The reaction mixture was solvent exchanged intoabout 80 mL of dichloromethane and washed successively with 0.1 N HCl(60 mL), saturated NaHCO₃ solution (60 mL) and a final brine wash (60mL). The organic layer was dried over Na₂SO₄ and filtered. After theremoval of the solvents, crude mixture of J/K was obtained. This crudemixture was dissolved in dichloromethane, washed twice with 0.1N HCl,once with water and once with brine followed by drying over sodiumsulfate, filtered and concentrated to obtain J/K). ¹H NMR (300 MHz,CDCl₃): δ 7.82 (d, J=9.0 Hz, 1H), 7.38 (m, 1H), 6.97 (dd, J=9.0, 3.0 Hz,1H), 6.82 (d, J=3.0 Hz, 1H), 5.88 (m, 1H), 5.22 (m, 2H), 3.91 (s, 3H),3.28 (td, J=12.0, 3.0 Hz, 2H). ¹⁹F NMR (282.2 MHz, CDCl₃): δ −100.3 ppm(J) and −100.8 ppm (K). LCMS: m/z=266.93.

Alternative reagents and reactions conditions to those disclosed abovemay also be employed. For example, when R═NH₂, other bases (e.g.,potassium/sodium hydroxide, potassium-tert-butoxide, sodium/potassiumtrimethylsiloxide) may be used. Other additives and alternative solvents(e.g., ethanol, ethanol/isopropyl acetate or toluene) may be employed.

In addition, alternative reagents and reactions conditions to thosedisclosed above may also be employed when R═NO₂. For example, iron, BHT,and AcOH may be used in combination with ethanol as solvent andtemperatures ranging from about 60° C. to about 70° C.

Step 4: Synthesis of IV

I. Chlorination of J to Provide Compound of Formula IV:

To a reaction vessel was charged J (7.4 g, 27.79 mmol, 1.0 equivalent)and DMF (148 mL). Phosphorus oxychloride (POCl₃) (4.2 mL, 44.47 m mol,1.6 equivalent) was charged over about 3 minutes maintaining thereaction temperature was kept below about 30° C. The reaction was heatedto about 75° C. until reaction completion. The reaction mixture wasslowly poured into 150 mL of water while maintaining the temperaturebelow about 25° C. Methyl-t-butyl ether (MTBE) (75 mL) was charged andthe phases separated. The aqueous phase was back-extracted with 4×75 mLof MTBE. The combined MTBE phases were washed successively withsaturated NaHCO₃ solution (200 mL) and saturated NaCl solution (150 mL)and dried over Na₂SO₄. After the removal of the solvents, the crudeproduct IV was isolated. The crude material was suspended in hexanes(4.3 volumes), heated to dissolution and slowly cooled to about 20° C.resulting in slurry formation of the desired regioisomer IV which wasthen isolated by filtration and dried. ¹H NMR (300 MHz, CDCl₃): δ 8.02(d, J=9.0 Hz, 1H), 7.48 (dd, J=9.0, 3.0 Hz, 1H), 7.34 (d, J=3.0 Hz, 1H),5.97 (m, 1H), 5.31 (m, 2H), 4.0 (s, 3H), 3.35 (td, J=12.0, 3.0 Hz, 2H).¹⁹F NMR (282.2 MHz, CDCl₃): δ −96.3 ppm (IV) and −97.1 ppm(regioisomer). LCMS: m/z=285.27.

Alternative reagents and reactions conditions to those disclosed abovemay also be employed. For example, other chlorinating agents (e.g.,trichloroisocyanuric acid, chlorine gas,1,3-dichloro-5,5-dimethylhydantoin, N-chlorosuccinimide, thionylchloride/DMF, oxalyl chloride/DMF) may be used. In addition, othersolvents, such as acetonitrile or acetic acid, as well hydrocarbonsolvents (e.g., toluene or heptane), ethers (e.g., methyl-t-butyl etheror THF), or chlorinated solvents (e.g., dichloromethane or chloroform)may be employed. Other amine additives (e.g., DABCO, triethylamine, orN-methylmorpholine) or phase transfer catalysts (e.g., benzyltrimethylammonium chloride) may also be employed. Further, temperaturesranging from about 20° C. to about 80° C. may be used.

Compounds G and H were synthesized as discussed above in route I.

Step 1: Synthesis of IV-b

I. Synthesis of IV-b from H

In a reaction vessel, triphenylphosphine (235.2 g, 896.3 mmol) wasdissolved in tetrachloride (300 mL) at ambient temperature. The solutionwas cooled to below about 5° C. followed by addition of triethylamine(73 mL, 523.7 mmol) and H (41.8 g active, 295.4 mmol). Aniline (32 mL,351.2 mmol) was then slowly added in about 30 minutes. The mixture wasagitated at below about 5° C. for about one hour, and allowed to warm toambient temperature. The solution was then heated to 50 to 55° C., atwhich point the reaction became exothermic. The reaction temperaturequickly rose up to about 92° C. without heating, with rigorous refluxingand gas evolution. The temperature was cooled to about 75° C., and themixture was agitated for about ten hours. To the reaction mixture wasadded heptane (700 mL) followed by concentration to remove about 700 mLof distillate. The second portion of heptane (700 mL) was added, and themixture was heated to reflux at about 100° C. for about 30 minutesbefore cooling to about 20° C. The mixture was agitated at about 20° C.for about 30 minutes, and then filtered. The filtered cake was mixedwith additional heptane (700 mL), heated to reflux for about 30 minutes,cooled to about 20° C., and agitated for about 30 minutes. The mixturewas filtered, and the two filtrates were combined, and concentrated toprovide crude IV-b The crude IV-b was used directly in the next stepwithout further processing. ¹H NMR (300 Hz, CDCl₃): δ 7.37-7.45 (m, 2H),δ 7.25 (tt, J=7.8, 0.9 Hz, 1H), δ 6.98 (dd, J=8.7, 1.2 Hz, 2H), δ5.82-5.96 (m, 1H), δ 5.35 (d, J=8.4 Hz, 1H), δ 5.30 (s, 1H), δ 3.07(tdt, J=15.9, 7.2, 1.2 Hz, 2H); ¹³C NMR (75 Hz, CDCl₃): δ 144.8, 139.7(t, J=36.7 Hz), 129.0, 127.7 (t, J=5.8 Hz), 126.4, 124.2 (t, J=282.8Hz), 121.7, 120.2, 39.5 (t, J=24.0 Hz).

Alternative reagents and reactions conditions to those disclosed abovemay also be employed. For example, other bases (e.g. diisopropylethylamine (DIPEA), pyridine, tributylamine, DBU, N-methylmorpholine (NMM))may be used. In addition, alternate halogenating agent (e.g.N-chlorosuccinimide, chlorine(g), chloramine-T) may be employed.Further, other solvents (e.g. dichloromethane, chloroform,chlorobenzene) can be used.

II. Synthesis of IV-b from G

a. Synthesis of IV-a from G

In a reaction vessel, G (10.0 g, 60.9 mmol) was dissolved in aniline (50mL, 548.7 mmol) at ambient temperature. The solution was heated toreflux at about 150° C. for about 24 hours under nitrogen. The mixturewas cooled to below about 5° C. followed by diluting with MTBE (100 mL).The pH was then adjusted to acidic by adding about 100 mL of 6N HClaqueous solution at below about 5° C. The mixture was allowed warming upto ambient temperature, settled, and separated. The aqueous phase wasextracted with MTBE (2×100 mL). The organic phases were combined, washedwith 1N HCl aqueous solution and 5% NaHCO₃ aqueous solution in sequence.The organic phase was filtered through a pad of Na₂SO₄, and concentratedto provide crude IV-a. ¹H NMR (300 Hz, CDCl₃): δ 7.95 (bs, 1H), δ 7.57(d, J=7.5 Hz, 1H), δ 7.37 (tt, J=8.7, 2.4 Hz, 1H), δ 7.19 (tt, J=7.8,1.2 Hz, 1H), δ 5.72-5.86 (m, 1H), δ 5.27-5.35 (m, 2H), δ 2.96 (tdt,J=17.1, 7.5, 1.2 Hz, 2H); ¹³C NMR (75 Hz, CDCl₃): δ 161.6 (t, J=28.7Hz), 135.9, 129.2, 127.0 (t, J=5.7 Hz), 125.6, 122.2, 120.2, 117.1 (t,J=254.3 Hz), 38.4 (t, J=24.0 Hz); M.P.: 48.0° C.; GCMS m/z (rel.intensity): 211 (100, M⁺).

Alternative reagents and reactions conditions to those disclosed abovemay also be employed. For example, other solvents (toluene, xylenes,chlorobenzene, acetonitrile) can be used.

b. Synthesis of IV-b from IV-a

The IV-a (6.1 g, 28.0 mmol) was dissolved in DCM (60 mL) in a reactionvessel at ambient temperature. Phosphorus pentachloride (10.8 g, 51.9mmol) was added in one portion. The mixture was agitated at ambienttemperature for about 16 hours. The reaction mixture was quenched byslowly transferring the mixture into 40% K₃PO₄ aqueous solution whilemaintaining the temperature below about 20° C. The pH of the aqueousphase was adjusted to about 7.5 by adding additional 40% K₃PO₄ aqueoussolution. The phases were separated, and the aqueous phase was extractedwith DCM (60 mL). The combined organic phases were filtered through apad of Na₂SO₄, and concentrated to provide crude IV-b. ¹H NMR (300 Hz,CDCl₃): δ 7.37-7.45 (m, 2H), δ 7.25 (tt, J=7.8, 0.9 Hz, 1H), δ 6.98 (dd,J=8.7, 1.2 Hz, 2H), δ 5.82-5.96 (m, 1H), δ 5.35 (d, J=8.4 Hz, 1H), δ5.30 (s, 1H), δ 3.07 (tdt, J=15.9, 7.2, 1.2 Hz, 2H); ¹³C NMR (75 Hz,CDCl₃): δ 144.8, 139.7 (t, J=36.7 Hz), 129.0, 127.7 (t, J=5.8 Hz),126.4, 124.2 (t, J=282.8 Hz), 121.7, 120.2, 39.5 (t, J=24.0 Hz).

Alternative reagents and reactions conditions to those disclosed abovemay also be employed. For example, other bases (e.g. sodium hydroxide,potassium hydroxide, potassium phosphate dibasic, potassium carbonate,sodium carbonate) may be used. In addition, alternate halogenating agent(e.g. N-chlorosuccinimide, chlorine(g), chloramine-T, phosphorousoxychloride, thionyl chloride) may be employed. Further, other solvents(e.g. dichloromethane, chloroform, chlorobenzene, toluene, acetonitrile)can be used.

Step 2: Synthesis of IV-c from IV-b

In a reaction vessel, IV-b (29.5 g active or 32 g crude, 128.2 mmol) wasdissolved in acetonitrile (500 mL) followed by addition of potassiumcyanide (8.5 g, 130.5 mmol). The mixture was vacuum degassed withnitrogen, and agitated at ambient temperature for about 16 hours. Themixture was concentrated under vacuum to remove acetonitrile completely,and then suspended in toluene (500 mL). The 5% NaHCO₃ aqueous solution(250 mL) was added to dissolve the inorganic salt. The mixture wassettled, and separated. The aqueous phase was extracted with toluene(250 mL). The organic phases were combined, filtered through a pad ofNa₂SO₄, and concentrated to provide crude IV-c. ¹H NMR (300 Hz, CDCl₃):δ 7.49 (tt, J=7.2, 1.8 Hz, 2H), δ 7.41 (tt, J=7.2, 1.2 Hz, 1H), δ 7.26(dt, J=7.2, 1.8 Hz, 2H), δ 5.79-5.92 (m, 1H), δ 5.37 (dd, J=5.1, 1.2 Hz,1H), δ 5.32 (s, 1H), δ 3.07 (tdt, J=16.5, 7.2, 1.2 Hz, 2H); ¹³C NMR (75Hz, CDCl₃): δ 146.0, 135.7 (t, J=35.5 Hz), 129.5, 127.0 (t, J=4.7),122.4, 120.9, 120.2, 117.3 (t, J=245.0 Hz), 108.9, 38.8 (t, J=24.1 Hz);GCMS m/z (rel. intensity): 220 (70, M⁺).

Alternative reagents and reactions conditions to those disclosed abovemay also be employed. For example, other bases (e.g. sodium hydroxide,potassium hydroxide, potassium phosphate dibasic, potassium carbonate,sodium carbonate) may be used. In addition, alternate cyanation agent(e.g. trimethylsilylcyanide, sodium cyanide, potassium ferricyanide,lithium cyanide) may be employed. Further, other solvents (e.g.dichloromethane, chloroform, chlorobenzene, toluene) can be used.

Step 3: Synthesis of IV-d from IV-c

In a reaction vessel, methoxy-o-phenylenediamine was mixed with toluene(41 mL) at ambient temperature followed by addition of acetic acid (14.2mL, 248 mmol). The black solution was vacuum degassed with nitrogen. Atabout 20° C., the prepared solution of IV-c (4.89 g active or 6.4 gcrude, 22.2 mmol) in toluene (11 mL) was slowly added into abovesolution in about three hours while maintaining the temperature at about20° C. The resulting mixture was then heated to about 30° C. for about64 hours. The reaction mixture was cooled to below about 20° C., andEtOAc (40 mL) was added followed by pH adjustment to about 9-9.5 withabout 76.5 mL of 3N NaOH aqueous solution. The mixture was filteredthrough diatomaceous earth (5 g) before settling and phase separation.The separated aqueous phase was extracted with EtOAc (80 mL). The twoorganic phases were combined, and activated charcoal (5 g) was added.The mixture was stirred at ambient temperature for about 16 hours, andfiltered through diatomaceous earth (5 g). The filtrate was concentratedunder vacuum to remove solvent completely, and IPA (20 mL) was added.The mixture was heated to dissolve the crude solid at about 40° C. Thesolution was heated to reflux for about 30 minutes, and then cooled toabout 20° C. The IV-d seed (5 mg) was added to induce thecrystallization. The suspension was agitated at about 20° C. for aboutone hour. Water (30 mL) was slowly added in about five hours whilemaintaining the temperature at about 20° C. The resulting suspension wasagitated at about 20° C. for over about 10 hours before filtering andwashing with 33% IPA/H₂O (15 mL). The cake was dried to provide IV-d. ¹HNMR (300 Hz, CDCl₃): δ 7.77 (d, J=8.7 Hz, 1H), δ 7.09 (dd, J=9.6, 3.0Hz, 1H), δ 6.98 (d, J=3.0 Hz, 1H), δ 5.93-6.07 (m, 1H), δ 5.25-5.37 (m,4H), δ 3.92 (s, 3H), δ 3.32 (tdt, J=17.4, 6.9, 1.2 Hz, 2H); ¹³C NMR (75Hz, CDCl₃): δ 162.3, 149.9, 144.1, 134.5 (t, J=30.9 Hz), 131.6, 130.4,128.9 (t, J=4.6 Hz), 122.6 (t, J=238.2 Hz), 120.9, 118.2, 104.0, 55.7,39.4 (t, J=24.1 Hz);

MP: 102.4° C.; LCMS m/z (rel. intensity) 265.70 (100, M⁺).

Alternative reagents and reactions conditions to those disclosed abovemay also be employed. For example, other solvents (e.g. dichloromethane,chloroform, chlorobenzene, toluene, acetonitrile) can be used andtemperatures ranging from 10 to 80° C. may be employed.

Step 4: Synthesis of IV from IV-d

In a reaction vessel, IV-d (5.0 g, 18.8 mmol) was dissolved in 100 mLDCM at ambient temperature. The solution was cooled to below about 5° C.followed by slow addition of 1M BCl3 in DCM (19 mL, 19 mmol) in about 15minutes. Then t-BuNO₂ (9 mL) was slowly added in about two hours whilemaintaining the temperature at below about 5° C. The mixture was allowedwarming up to ambient temperature, and agitated for about 12 hours. Uponreaction reaching completion, the mixture was concentrated under vacuumto remove solvent, and then dissolved in EtOAc (100 mL). The solutionwas cooled to below about 5° C. followed by slow addition of 5% NaHCO₃aqueous solution. The resulting mixture was allowed warming up toambient temperature, settled, and separated. The aqueous phase wasextracted with EtOAc (2×100 mL). To the combined organic phase was addedactivated charcoal (2.0 g), and the mixture was agitated for about 16hours before filtering through diatomaceous earth (5 g). The filtratewas concentrated under vacuum to remove solvent completely, and IPA (25mL) was added. The mixture was heated to reflux for about 30 minutes,and then slowly cooled down. IV seed (5 mg) was added at 35-40° C. toinduce the crystallization. The mixture was cooled to about 20° C., andagitated for about two hours. Water (10 mL) was slowly added in abouttwo hours. The mixture was agitated for about one hour, and then cooledto below about 5° C. The mixture was agitated at below about 5° C. forabout one hour, then filtered and washed with 50% IPA/H₂O (15 mL). Thecake was dried to provide IV. ¹H NMR (400 Hz, CDCl₃): δ 8.00 (d, J=9.2Hz, 1H), δ 7.45 (dd, J=9.6, 2.8 Hz, 1H), δ 7.32 (d, J=2.8 Hz, 1H), δ5.91-6.01 (m, 1H), δ 5.23-5.34 (m, 2H), δ 3.98 (s, 3H), δ 3.32 (tdt,J=16.8, 7.2, 1.2 Hz, 2H);

¹³C NMR (400 Hz, CDCl₃): δ 162.8, 144.7, 143.9, 142.9 (t, J=29.7 Hz),134.9, 130.4, 128.6 (t, J=4.6 Hz), 124.3, 122.4, 120.0 (t, J=241.8 Hz),105.5, 56.0, 40.2 (t, J=24.5 Hz); MP: 82.8° C.; LCMS m/z (rel.intensity): 284.69 (100, M⁺).

Alternative reagents and reactions conditions to those disclosed abovemay also be employed. For example, other bases (e.g. sodium hydroxide,potassium hydroxide, potassium phosphate dibasic, potassium carbonate,sodium carbonate) may be used. Further, other solvents (e.g.dichloromethane, chloroform, chlorobenzene, toluene, acetonitrile) canbe used.

C. Synthesis of(S)-2-((((1R,2R)-2-allylcyclopropoxy)carbonyl)amino)-3,3-dimethylbutanoicacid (S)-1-Phenylethan-1-amine Salt (VII)

Compound VII was synthesized via two different routes as discussedbelow.

Compound of formula VII was obtained from 5-bromo-pent-1-ene viaKulinkovich cyclopropanation, acylation and enzymatic resolution. Thecyclopropanol and then cyclopropyl acetate were distilled but it was notnecessary to do so. Acid-base extractions were used to remove stillacetylated material. The final product was isolated as aS-1-phenylethanamine salt which improved the diastereomeric and overallpurity of the product. Recrystallization may be used to further improvethe purity of the product. Other salts may be possible.

Step 1: Synthesis of (1R,2R)-2-allylcyclopropan-1-ol (M1)

Kulinkovich reaction, acetylation and enzymatic resolution:

I. Kulinkovich Reaction with Ethyl Formate and 5-bromo-1-pentene

To a reaction vessel was added magnesium turnings (2.45 equivalents) andMeTHF (8 volumes). The flask was then sparged with nitrogen and5-bromo-1-pentene (2.4 equivalents) was added to the addition funnel.The mixture was heated to about 60° C. and 0.05 volumes of5-bromo-1-pentene were dripped into the mixture to initiate thereaction. Once the reaction initiated, the remaining portion of5-bromo-1-pentene was slowly added into the flask over about 3 hours.After the addition, the reaction was allowed to stir at about 60° C. forabout 1 hour after which Grignard L was cooled to room temperature. In aseparate flask was added ethyl formate (1.0 equivalent) and titaniumisopropoxide (0.5 equivalents) in MeTHF (2 volumes) under nitrogen. Themixture was cooled to about 0° C. and slowly the Grignard L was addedinto the flask over 3 hours. Upon complete addition, the reactionmixture was allowed to warm to room temperature and the reaction wasstirred for about 12 hours. The mixture was then cooled to about 0° C.and 4M sulfuric acid (10 volumes) was added slowly. The slurry wasstirred for 30 minutes after which the salts were dissolved. The mixturewas then polished filtered. The biphasic mixture was separated and theorganic layer was then washed twice with 10 wt. % sodium bicarbonate (10volumes) and once with water (10 volumes). The organic layer isconcentrated under reduced pressure at about 0° C. to obtain crude2-allylcyclopentanol M. ¹H NMR (400 MHz, CDCl₃): δ 5.53-5.43 (m, 1H),4.76-4.70 (m, 1H), 4.65-4.59 (m, 1H), 2.90-2.86 (m, 1H), 1.75 (br s,1H), 1.65-1.51 (m, 2H), 0.69-0.59 (m, 1H), 0.40-0.35 (m, 1H), 0.05-0.01(m, 1H).

Alternative reagents and reactions conditions to those disclosed abovemay also be employed. For example, other aprotic solvents (e.g.,tetrahydrofuran or diethyl ether) may be used. In addition, othertitanium catalysts, such as Titanium(IV) alkoxides (e.g., MeTi(OiPr)₃,MeTi(OtBu)₃, ClTi(OiPr)₃, ClTi(OtBu)₃, or Ti(OtBu)₄) may be employed.Further, temperatures ranging from about −20° C. to about 100° C. may beused.

II. Acetylation of 2-allylcyclopentanol (+/−)-M:

Into a reaction vessel was added 2-allylcyclopentanol M (1 equivalent)in MeTHF (10 volumes). The vessel was purged with nitrogen and thesolution was then cooled to 0° C. Triethylamine (3.0 equivalents) wasthen slowly added to the solution over about 30 minutes. The mixture wasallowed to stir for about 30 minutes after which acetyl chloride (2.5equivalents) was added maintaining the internal temperature about below20° C. The reaction was then allowed to stir for at least 12 hours atabout 21° C. After the allotted time, water (6 volumes) was slowlycharged to the reactor and the phases were separated. The organic layerwas then washed with 2M hydrochloric acid (6 volumes), 10 wt. % sodiumbicarbonate (6 volumes) and then brine (6 volumes). The organic layer isconcentrated under reduced pressure at about 0° C. to obtain cruderacemic 2-allylcyclopropyl acetate N. ¹H NMR (400 MHz, CDCl₃): δ5.85-5.73 (m, 1H), 5.10-5.04 (m, 1H), 5.00-4.97 (m, 1H), 3.85-3.82 (m,1H), 2.13-2.07 (m, 1H), 1.99 (s, 3H), 2.01-1.89 (m, 1H), 1.14-1.03 (m,1H), 0.87-0.76 (m, 1H), 0.64-0.57 (m, 1H).

Alternative reagents and reactions conditions to those disclosed abovemay also be employed. For example, other acetylating agents, such asacetic anhydride may be used. In addition, other acyl groups could beused for the enzymatic resolution, such as alkyl homologs (e.g., C1-C10)or aromatic groups (e.g., benzoate, substituted benzoates, ornaphthoates). Further, other amine bases (e.g.,N,N′-diisopropylethylamine, pyridine or piperidine), metal hydrides(e.g., sodium hydride and potassium hydride), alkoxides (e.g., sodiumtert-butoxide, lithium tert-butoxide, or potassium tert-butoxide) can beused. Other halogenated solvents (e.g., dichloromethane ordichloroethane), and combinations of these with 2-methyltetrahydrofuranor tetrahydrofuran can also be employed. In addition, other temperatureranges between about −20° C. to about 80° C. can be employed.

III. Enzymatic Resolution of 2-allylcyclopentanol

To a reaction vessel was charged 2-allylcyclopropyl acetate N in MeTHF(2 volumes) and MTBE phosphate buffer solution (10 volumes). The MTBEphosphate buffer solution was prepared by first dissolving potassiumphosphate dibasic (283 g) and potassium phosphate monobasic (104.8 g) inwater (1.6 L). MTBE (800 mL) was added to the solution and the biphasicmixture was stirred at about 21° C. for about 1 hour. The organic layerwas then separated and used as the MTBE phosphate buffer solution. Thereaction mixture was then cooled to about 0° C. and solid supportedNovozyme 435 (1.7 wt. %) was charged. The reaction was allowed to stirat about 0° C. for about 6 hours after which the mixture was filtered.The filtrate was then concentrated under reduced pressure at about 0° C.to obtain the majority as (1R,2R)-2-allylcyclopropan-1-ol M1 and theracemic (1S,2S)-2-allylcyclopropan-1-ol in a 10:1 to 15:1 mixture as amixture of the corresponding remaining acylated starting materials. Thecrude mixture was carried forward as is.

Alternative reagents and reactions conditions to those disclosed abovemay also be employed. For example, ethereal solvents (e.g.,tetrahydrofuran (THF), methyl tetrahydrofuran (MeTHF), diethyl ether(Et₂O) or 1,4-dioxane), water miscible solvents (e.g., methanol, ethanoland isopropanol), or other organic solvents (e.g., acetone, oracetonitrile) may be used. In addition, other deacylating lipases may beemployed. Further, temperatures ranging from about −20° C. to about 20°C. may be used.

Step 2: Synthesis of VII

I. Coupling to VII

A solution of alcohol M1 in MTBE and MeTHF (contains 14 g of desiredalcohol) was charged to a reactor. DMF (140 mL) and N,N′-disuccinimidylcarbonate (DSC) (47.5 g, 1.3 eq) were charged to the reactor to obtain athin slurry. Pyridine (11.3 g, 1 eq) was charged and the reactionmixture was heated to about 45° C. Upon reaction completion, thereaction mixture was cooled to about 0° C. and quenched with water (196mL). The reaction mixture was stirred for at least 30 minutes.Succinimide O could be optionally isolated by extraction with ethylacetate, washing the organic layer and solvent removed by distillation,or used directly without purification in the subsequent step. ¹H NMR(400 MHz, CDCl₃): δ 5.83-5.74 (m, 1H), 5.12-4.99 (m, 2H), 4.13-3.99 (m,1H), 2.81 (s, 4H), 2.13-1.92 (m, 2H), 1.39-1.30 (m, 1H), 1.11-1.04 (m,1H), 0.73-0.68 (m, 1H).

Continuing through with crude succcinate intermediate O, tert-leucine(23.4 g, 1.25 eq) and K₃PO₄ (84.8 g, 2.8 eq.) were charged to thereactor. The resulting mixture was warmed to room temperature and theresulting solution was stirred for about 18 h. Upon reaction completion,the mixture was diluted by MTBE (210 mL) and pH adjusted to pH 3 with 6MHCl (˜180 mL). The layers were separated and the organic layer was pHadjusted to pH >10 with 2.5M NaOH (˜70 mL). The aqueous layer wasremoved and the organic layer was washed with 0.5 M NaOH (100 mL). Thecombined basic aqueous layers was readjusted to pH <3 with 6M HCl (˜50mL) and washed twice with MTBE (100 mL×2).

The combined organic layers were solvent swapped to MTBE (107 mL). In aseparate container, S(−) 1-phenylethylamine (10.9 g, 1 eq.) wasdissolved in MTBE (32.7 mL). The solution of the amine was chargedslowly to the solution containing the succinimide intermediate. A smallamount of VII (S)-1-phenylethan-1-amine salt (0.055 g, 0.5%) was chargedfollowed by the rest of the amine solution. The slurry was agedovernight to obtain a thick slurry. The resulting slurry was filteredand rinsed with MTBE (50 mL). The solids were dried in the vacuum ovenuntil constant weight was reached to obtain VII as the(S)-1-phenylethan-1-amine salt. NMRs of the free acid: ¹H NMR (400 MHz,CDCl₃) δ 7.4 (m, 5H), 6.3 (broad s, 3H), 5.8 (m, 1H), 5.3 (d, 1H), 5.1(d, 1H), 4.2 (q, 1H), 3.8 (d, 1H), 3.7 (m, 1H), 2.1 (m, 1H), 1.9 (m,1H), 1.5 (d, 3H), 1.1 (m, 1H), 0.9 (d, 9H), 0.8 (m, 1H), 0.5 (q, 1H).¹³C-NMR (CDCl₃) δ 173.1, 157.0, 115.7, 63.3, 53.9, 36.2, 34.9, 33.7,27.1, 17.3, 11.7.

Alternative reagents and reactions conditions to those disclosed abovemay also be employed. For example, polar aprotic solvents (e.g.,dimethylacetamide) and temperatures ranging from about 25° C. to about65° C. may be employed. In addition, alternative crystallization solventsystems (e.g., acetonitrile) can be used.

The route II shown above differs from route I in the formation ofintermediate M3 and its conversion to M1. The synthesis of M3 and itsconversion to VII are discussed below.

Synthesis of M3 from M2

To a reaction vessel was charged alcohol M2 (100.0 g, 1019.0 mmol,alcohol M2 comes as a solution in MTBE along with an acetate impurity N1from the previous enzymatic resolution step. The actual amount ofsolution that was charged was calculated after determining the wt % ofthe enzymatic resolution solution and then adjusting the charge toensure that 100.0 g of alcohol was present within that charge.). To thiswas charged dichloromethane (300 mL) and triethylamine (134.0 g, 1324.6mmol). The reaction was cooled to an internal temperature of about 0° C.In a separate flask, 3,5-dinitrobenzoyl chloride (305.4 g, 1324.6 mmol)was dissolved in dichloromethane (300 mL). The dinitrobenzoyl chloridestream was then charged to the alcohol stream over approximately 15minutes maintaining an internal temperature below about 5° C. Thecombined mixture was aged for approximately 4 h. The reaction mixturewas allowed to warm to room temperature and then water (600 mL) wasadded and the phases were vigorously agitated to ensure good mixing ofthe phases. The phases were allowed to settle and the bottom phase wasseparated and washed an additional two times with water (600 mL). To thefinal organic phase was charged silica gel (200 g), and the slurry wasallowed to age at room temperature for approximately 30 minutes. Theslurry was filtered and the silica gel cake was washed with 20 vol %isopropyl alcohol in heptane (amount of wash solution is determined byeluting with 4× the volume of the silica pad.) The combined filtrate andwashes were concentrated by rotary evaporation to an approximate volumeof 200 mL. Isopropyl alcohol (600 mL) was charged to the concentratedstream and distilled back down by rotary evaporation to an approximatevolume of 200 mL. This process was repeated until less than 5%dichloromethane in comparison to isopropyl alcohol was observed by ¹HNMR. Heptane was then charged to the reaction mixture to reach a finalvolume of approximately 500 mL. The mixture was then heated to aninternal temperature of about 45° C. The crystallization was then seededwith 0.5 wt % (500 mg) of ester M3 seeds. The reaction was then cooledto about 0° C. over about 5 h and aged at that temperature for at leastabout 12 h. The resulting slurry was filtered and the cake was washedwith hepatane (100 mL). The isolated solids were then dried under vacuumat about 21° C. to afford M3. ¹H NMR (400 MHz, CDCl₃): δ 9.22-9.21 (m,1H), 9.11-9.10 (m, 2H), 5.95-5.85 (m, 1H), 5.17-5.05 (m, 2H), 4.27-4.24(m, 1H), 2.22-2.07 (m, 2H), 1.41-1.33 (m, 1H), 1.14-1.09 (m, 1H),0.85-0.80 (m, 1H); HRMS calc'd C₁₃H₁₃N₂O₆ [M+H]⁺: 293.0774 found:293.0777.

Alternative reagents and reactions conditions to those disclosed abovemay also be employed. For example, other bases (e.g., di-isopropyl ethylamine, N-methyl morpholine) and other solvents (e.g. chloroform,tetrahydrofuran, MTBE, 2-methyl tetrahydrofuran, cyclopentyl methylether) can be used.

Hydrolysis of M3 to M1

To a reaction vessel was charged M3 (100.0 g, 342.2 mmol) and this wasdissolved in tetrahydrofuran (300 mL). To this was charged sodiumhydroxide (300 mL of a 1.0 M aqueous solution) and the resulting mixturewas stirred at room temperature for about 1 h. Toluene (200 mL) wascharged to the reaction followed by HCl (120 mL of a 1.0 M aqueoussolution.) The phases of the resulting biphasic mixture were split andthe organic phase was washed with sodium bicarbonate (120 mL of a 5 wt %aqueous solution.) The phases were split again and the organic layer waswashed twice with water (200 mL). The final organic phase was washedwith brine (200 mL of 10 wt % aqueous solution), dried over MgSO₄, andthen filtered. The final solution of alcohol M1 was used in thesubsequent step without further purification.

Alternative reagents and reactions conditions to those disclosed abovemay also be employed. For example, other bases (e.g., potassiumhydroxide, tetrabutyl ammonium hydroxide) and other solvents (e.g.2-Methyl tetrahydrofuran, MTBE, toluene) can be used.

Synthesis of O from M1

To a reaction vessel was charged the toluene solution of alcohol M1 (theamount of solution charged was determined by obtaining a wt % by ¹H NMRof the alcohol in solution and then charging the amount necessary tohave 28.0 g, 285.3 mmol of alcohol M1 in the reaction.) To this wascharged pyridine (29.3 g, 370.9 mmol) followed by N,N′-Disuccinimidylcarbonate (116.9 g, 456.5 mmol). The resulting heterogeneous reactionmixture was heated to 45° C. and stirred at this temperature for 4 h.The reaction was then cooled to room temperature and water (170 mL) wascharged. The mixture was agitated at room temperature for 30 min andthen the phases were split. The final toluene solution is used withoutfurther purification in the subsequent step. In this fashion, O (52.9 gdetermined by ¹H NMR wt % assay, 221.3 mmol, 77.6%) was synthesized.

Alternative reagents and reactions conditions to those disclosed abovemay also be employed. For example, other bases (e.g., di-isopropylamine, triethylamine, di-isopropyl ethyl amine) and other solvents (e.g.xylenes, chlorobenzene, MTBE) can be used. Also, temperatures rangingfrom about 0° C. to about 110° C. may be employed.

Synthesis of VII from O

To a reaction vessel was charged a toluene solution of carbonate O (theamount of solution charged was determined by obtaining a wt % by ¹H NMRof the carbonate in solution and then charging the amount necessary tohave 9.9 g, 41.4 mmol of carbonate O in the reaction.). Additionaltoluene was charged to the reaction to bring the final reaction volumeup to 60 mL. To this solution was charged di-isopropyl ethyl amine (10.7g, 82.8 mmol) and L-tert-leucine (6.0 g, 45.52 mmol). The reactionmixture was heated to about 45° C. and agitated at this temperature forabout 6 h. The reaction was then cooled to room temperature andhydrochloric acid (60 mL of a 3N aqueous solution) was charged. Thebiphasic mixture was agitated for about 30 min at room temperature andthen the phases were split. The organic rich stream was thenconcentrated to approximately 20 mL by rotary evaporation and then 80 mLof acetonitrile was added. Concentration down to 20 mL and thenrecharging of acetonitrile was continued until the amount of toluene isabout <5% v/v. The final stream is adjusted to a volume of 80 mL usingacetonitrile and heated to about 50° C. The mixture is then heated toabout 50° C. and (S)-phenethylamine (6.0 g, 49.7 mmol as a solution in30 mL of acetonitrile at 50° C.) was charged. The reaction mixture wasseeded with 0.5 wt % seeds of VII (0.05 g) and the thin slurry was agedfor 1 h at 50° C. The mixture was then cooled down to room temperatureover about 3 h and the resulting slurry was aged for at least about 12h. The solids were collected by filtration and the cake was washed withabout 20 mL of acetonitrile. The final wet cake was dried in the oven atabout 40° C. under vacuum to afford VII.

Alternative reagents and reactions conditions to those disclosed abovemay also be employed. For example, other bases (e.g., potassiumcarbonate, sodium carbonate, potassium phosphate tribasic) and othersolvents (e.g. dimethylformamide, dimethylacetamide) can be used. Also,other salt form in h amines (e.g. (R)-phenethylamine, D-phenylalaninol,(1S,2S)-(+)-2-amino-1-(4-nitrophenyl)-1,3-propanediol,(S)-(+)-2-phenylglycinol) may be employed.

D. Synthesis of(1R,2R)-1-Amino-2-(difluoromethyl)-N-((1-methylcyclopropyl)sulfonyl)cyclopropane-1-carboxamideHydrochloride Salt (XII)

The existing process route shown above was disclosed is in the U.S.Publication No. 2014-0017198. The route shown below proceeds through acommon known intermediate V-v. This intermediate V-v was synthesizedusing two alternative schemes. In the first scheme, racemic A-b wasselectively hydrolyzed to racemic (±)-A-c with an approximate 10:1 ratioof cis/trans diastereomers. This mono acid is subjected to a classicalresolution with a chiral amine to form chiral A-c as a salt. Arecrystallization can be performed to enhance enantiomeric excess. Thecarboxylic acid was next converted to the amide A-d and isolated. Intelescoping steps, the amide was subjected to a Hoffman rearrangement,hydrolysis to the amine, protection of the amine with Boc and hydrolysisof the methyl ester to form the desired amino acid, V-v. V-v was thenconverted to XII as shown in the above scheme.

First Alternative Scheme for Intermediate V-v Used to Synthesize XII

Synthesis of(1S,2R)-2-(Difluoromethyl)-1-(isopropoxycarbonyl)cyclopropane-1-carboxylicacid (A-c)

Synthesis of(1S,2R)-2-(difluoromethyl)-1-(isopropoxycarbonyl)cyclopropane-1-carboxylicacid (B) Step 1: Synthesis of Intermediate Z

To a reactor was charged difluoroacetaldehyde ethyl hemiacetal Y (100 g,0.79 mole), cyclopentyl methyl ether (CPME, 500 mL, 5 mL/g) anddiisopropyl malonate (150 mL, 1 eq.). To the resulting solution, held atabout 20° C., was added triethylamine (Et₃N, 100 mL, 1 mL/g). Themixture was warmed to about 35° C. and stirring was continued for about20 hours. Upon reaction completion, a small sample was taken from thisCPME solution of alcohol Z and washed with 1M aq. KH₂PO₄ until the pHwas decreased to −7 followed by brine. The organic layer was dried overMgSO₄ and concentration to dryness under vacuum. The residue waspurified via column chromatography on silica gel using a gradient of 0%to 25% MTBE in hexanes to afford a clean sample of alcohol Z. ¹H NMR(300 MHz, CDCl₃): δ 1.275-1.30 (m, 12H), 3.63 (d, J=4.5 Hz, 1H), 3.95(d, J=7.8 Hz, 1H), 4.32-4.45 (m, 1H), 5.06-5.20 (m, 2H) and 5.93 (dt,J=55.4 Hz and 4.2 Hz). ¹⁹F NMR (282 MHz, CDCl₃): δ −129.0 (m). LCMS:(m/z) 291.1 (M+Na), 269.1 (M+H).

Alternative reagents and reactions conditions to those disclosed abovemay also be employed. For example, other ethereal solvents (e.g., THF,MeTHF, or MTBE) may be employed. In addition, temperatures ranging fromabout 0° C. to about 60° C. may be used. In addition, other organicamines (e.g., DIPEA) and malonate ester analogs (e.g., methyl, ethyl,benzyl, and a variety of other esters) may be employed.

Step 2: Synthesis of Intermediate A-a from Z

The bulk of the CPME solution of alcohol Z was cooled to about 20° C.followed by addition of acetic anhydride (Ac₂O, 200 mL, 2 mL/g) and4-(dimethylamino)pyridine (DMAP, 4.83 g, 0.05 eq.) which resulted in anexotherm up to about 50° C. The resulting solution was stirred for about20 hours at about 20° C. Upon reaction completion, 1M aq. K₂HPO₄ (1.0 L,10 mL/g) was added which resulted in an exotherm. After 15 minutes thelayers were separated. The CPME layer was washed with 1M aq. K₂HPO₄ (500mL, 5 mL/g), a mixture of 1:1 (100 mL) 1M aq. K₂HPO₄ and 1M aq. KH₂PO₄and brine (500 mL, 5 mL/g). To the CPME solution was added CPME (500 mL,5 mL/g) and the volume was reduced to ˜400 mL (4 mL/g) via distillationunder vacuum. A small sample was taken, from this CPME solution ofolefin A-a and this solution was concentrated to dryness under vacuum.The residue was purified via column chromatography on silica gel using agradient of 0% to 15% MTBE in hexanes to afford a clean sample of olefinA-a. ¹H NMR (300 MHz, CDCl₃): δ 1.25-1.29 (m, 12H), 5.06-5.21 (m, 2H),6.50 (dt, J=54.6 Hz and 5.72 Hz) and 6.67-6.75 (m, 1H). ¹⁹F NMR (282MHz, CDCl₃): δ −114.4 (m). GCMS: (m/z) 251 (M+H).

Alternative reagents and reactions conditions to those disclosed abovemay also be employed. For example, other ethereal solvents (e.g., THF,MeTHF, or MTBE) or non-ethereal solvents (e.g. toluene) may be employed.In addition, strong organic bases (e.g., DBU) may also be used. Further,other activating groups (e.g., triflic anhydride, mesyl chloride, ortoluene sulfonyl chloride) and temperatures ranging from about 0° C. toabout 60° C. may be employed.

Step 3: Synthesis of A-b from A-a

To a reactor was charged trimethylsulfoxonium iodide (Me₃SOI, 200 g,1.15 eq.), potassium tert-butoxide (KOtBu, 97.5 g, 1.0 eq.) anddimethylsulfoxide (DMSO, 500 mL, 5 mL/g). The resulting suspension wasstirred at about 25° C. for about 4 hours after which a clear solutionwas formed. To this DMSO solution was slowly added the CPME solution ofolefin C in such a rate so not to exceed about 55° C. The resultingsuspension was stirred overnight at about 25° C. The temperature wasdecreased to about 20° C. followed by addition of 1M aq. H₂SO₄ (1.0 L,10 mL/g) which resulted in an exotherm. After 15 minutes the layers wereseparated. To the organic layer was added CPME (400 mL, 4 mL/g) and 10%aq. K₂CO₃ (500 mL, 5 mL/g). The layers were separated. The organic layerwas washed with water (250 mL, 2.5 mL/g) followed by addition of CPME(200 mL, 2 mL/g) and reduction of volume to ˜500 mL (˜5 mL/g) viadistillation under vacuum. To the resulting suspension was addedcharcoal (5.0 g, 0.05 g/g). The resulting suspension was filteredthrough diatomaceous earth followed by a rinse with CPME (200 mL, 2mL/g). A small sample was taken from the CPME solution of cyclopropaneA-b and was concentrated to dryness under vacuum and analyzed. Theresidue was purified via column chromatography on silica gel using agradient of 0% to 15% MTBE in hexanes to afford a clean sample ofcyclopropane A-b. ¹H NMR (300 MHz, CDCl₃): δ 1.24-1.30 (m, 12H),1.46-1.51 (m, 1H), 1.69-1.74 (m, 1H), 2.26-2.40 (m, 1H), 5.01-5.14 (m,2H) and 5.68 (dt, J=56.0 Hz and 5.1 Hz). ¹⁹F NMR (282 MHz, CDCl₃): δ−114.1 (m). GCMS: (m/z) 223 (M+H). LCMS: (m/z) 287.1 (M+Na), 265.1(M+H).

Alternative reagents and reactions conditions to those disclosed abovemay also be employed. For example, DMSO mixtures with other non-proticsolvents (e.g., THF, MeTHF, or MTBE) and temperatures ranging from about0° C. to about 60° C. may be employed. Further, strong base, such as NaHmay be used.

Step 4: Synthesis of Intermediate A-c from A-b Synthesis of(1S,2R)-2-(Difluoromethyl)-1-(isopropoxycarbonyl)cyclopropane-1-carboxylicacid (A-c)

The CPME solution of cyclopropane A-b was diluted with isopropanol (IPA,800 mL) and the volume was reduced to ˜400 mL via distillation undervacuum. The resulting solution was cooled to about −3° C. followed byaddition of 35% aq. tetraethylammonium hydroxide (Et₄NOH, 266 mL, 0.80eq.) was added in such a rate not to exceed about 0° C. The reactionmixture was stirred overnight. 1M aq. HCl (200 mL) was slowly added insuch a rate not to exceed about 5° C. followed by water (400 mL). Thetemperature was increased to about 15° C. and CPME (200 mL) was added.The layers were separated. The pH of the aqueous layer was checked andproved to be ˜6.5. The CPME layer was extracted with 0.5M aq. K₂CO₃ (100mL). Both aqueous layers were combined followed by addition of conc.H₂SO₄ (20 mL) which lowers the pH to ˜2. Next CPME (400 mL) was addedand the layers were separated. The CPME layer was extracted twice with0.5M aq. K₂CO₃]. Both aqueous layers were combined and acidified to pH˜2 with H₂SO₄ (20 mL). Next CPME (500 mL) was added. Layers wereseparated. The CPME layer was washed with water (250 mL) followed byaddition of CPME (400 mL). The volume was reduced to ˜500 mL viadistillation under vacuum. At this point activated charcoal (5.0 g) wasadded and the resulting suspension was filtered through diatomaceousearth followed by a rinse with CPME (100 mL). The volume was againreduced to ˜500 mL via distillation under vacuum. A small sample wastaken from this CPME solution of half ester/acid (±)-A-c and the CPAsalt was formed. The solids were obtained via filtration. The solidswere suspended in CPME and 1M aq. NaOH. After all the solids weredissolved the layers were separated. The aq. layer was acidified withconc. H₂SO₄ to pH ˜2 and half ester/acid (±)-A-c was extracted intoCPME. This solution was concentrated to dryness under vacuum to afford aclean sample of half ester/acid (±)-A-c. ¹H NMR (300 MHz, CDCl₃): δ 1.31(d, J=6.3 Hz, 5H), 1.91-1.98 (m, 2H), 2.52-2.59 (m, 1H), 5.15-5.24 (m,2H) and 5.80 (dt, J=55.7 Hz and 6.3 Hz). ¹⁹F NMR (282 MHz, CDCl₃): δ−111.9 (m). LCMS: (m/z) 443.0 (2M−H), 220.9 (M−H).

To the solution of half ester/acid (±)-A-c in CPME was added(R)-(+)-1-(4-methylphenyl)ethylamine (62.5 mL, 0.55 eq.) which resultedin an exotherm. Next, seeds of A-c (100 mg) in heptane (20 mL) wereadded followed by heptane (500 mL, 5 ml/g). After the suspensionthickened the temperature was increased to about 50° C. After stirringovernight the temperature was decreased to about 25° C. over about 5hours. Next the temperature was decreased to 0° C. to 5° C. and held atthat temperature for about 1 hour. The solids were collected viafiltration and rinsed with 33% CPME in heptane (250 mL, 2.5 mL/g). Thesolids were dried in a vacuum oven at about 40° C. to constant weight toafford the salt of half ester/acid A-c. This material was suspended inCPME (500 m, 10 mL/g) and heated to about 70° C. at which point a clearsolution was obtained. This solution was cooled to about 65° C. followedby addition of seeds. The resulting suspension was cooled to about 50°C. over about 3 hours. The resulting thick suspension was held at about50° C. overnight. The temperature was decreased to about 30° C. overabout 4 hours followed by decreasing the temperature to 0° C. to 5° C.and holding at that temperature for about 1 hour. The solids wereobtained via filtration followed by a rinse with 50% CPME in heptane(100 mL). The solids were dried at about 40° C. in a vacuum oven toconstant weight to afford the salt of half ester/acid A-c. ¹H NMR (300MHz, DMSO-d₆): δ 1.08-1.17 (m, 7H), 1.44 (d, J=6.3 Hz, 3H), 1.86-1.90(m, 1H), 2.30 (s, 3H), 4.23-4.30 (m, 1H), 4.81-4.89 (m, 1H), 5.70 (dt,J=56.3 Hz and 6.0 Hz, 1H), 7.20 (d, J=7.5 Hz, 2H) and 7.35 (d, J=7.5 Hz,2H. ¹⁹F NMR (282 MHz, DMSO-d₆): δ −111.4 (m).

Both mother liquors were combined and extracted twice with 0.5M aq.K₂CO₃ (500 mL). Both aqueous layers were combined and acidified withH₂SO₄ (30 mL, 0.3 mL/g) to pH ˜2 in such a rate not to exceed about 30°C. Next CPME (500 mL) was added and the layers were separated. The CPMElayer was washed with water (250 mL). Next CPME (600 mL) was added andthe volume was reduced to ˜500 mL via distillation under vacuum. Nextcharcoal (5.0 g) was added and the resulting suspension was filteredthrough diatomaceous earth followed by a rinse with CPME (100 mL). Thevolume of the filtrate was reduced to ˜500 mL via distillation undervacuum. Next (S)-(−)-1-(4-methylphenyl)ethylamine (51 mL, 0.45 eq.) wasadded which resulted in an exotherm. To the resulting solution wereadded seeds (100 mg) followed by heptanes (500 mL). After about 1 hourthe resulting suspension was heated to about 60° C. After about 1.5hours the temperature was decreased to about 50° C. over about 1 hour.The resulting suspension was held at about 50° C. overnight.

The temperature was decreased to about 25° C. over about 5 hours. Thetemperature was further decreased to about 0° C. to about 5° C. and heldat that temperature for about 1 hour. The solids were collected viafiltration and rinsed with 33% CPME in heptane (200 mL). The solids weredried in a vacuum oven at about 40° C. to constant weight to afford thesalt of half ester/acid A-c. This material was suspended in CPME (500mL) and heated to about 75° C. at which point a clear solution wasobtained. This solution was cooled to about 65° C. followed by additionof seeds. The resulting suspension was cooled to about 50° C. over about5 hours. The resulting thick suspension was held at about 50° C.overnight. The temperature was then decreased to about 30° C. over about4 hours followed by decreasing the temperature to 0° C. to 5° C. andholding at that temperature for about 1 hour. The solids were obtainedvia filtration followed by a rinse with 50% CPME in heptane (110 mL).The solids were dried at about 40° C. in a vacuum oven to constantweight to afford the salt of half ester/acid A-c. ¹H NMR (300 MHz,DMSO-d₆): δ 1.08-1.17 (m, 7H), 1.44 (d, J=6.3 Hz, 3H), 1.86-1.90 (m,1H), 2.30 (s, 3H), 4.23-4.30 (m, 1H), 4.81-4.89 (m, 1H), 5.70 (dt,J=56.3 Hz and 6.0 Hz, 1H), 7.20 (d, J=7.5 Hz, 2H) and 7.35 (d, J=7.5 Hz,2H. ¹⁹F NMR (282 MHz, DMSO-d₆): δ −111.4 (m).

Alternative reagents and reactions conditions to those disclosed abovemay also be employed. For example, other alcoholic solvents matching theremaining ester may be used. In addition, other soluble hydroxides inIPA (e.g., KOH) and additional phase transfer catalysts (e.g.,tetrabutylammonium hydroxide) may be employed. Further, other chiralamines that lead to crystalline salts of the correct productstereoisomer and temperatures ranging from about −20° C. to about 60° C.may be used.

Synthesis of V-v from A-c

Synthesis of A-d from A-c

The salt of half ester/acid A-c (35 g, 97.9 mmol) was suspended in CPME(105 mL) and 1M aq. HCl (105 mL). The resulting suspension was stirredto the point that all solids were dissolved. The layers were separatedand the CPME layer was washed with 1M aq. HCl (35 mL) and brine (70 mL)followed by drying over Na₂SO₄ and concentration under vacuum. To theresulting solution was slowly added 1,1′-carbonyl-diimidazole (CDI, 19.9g, 1.25 eq.) in such a rate as to control off-gassing. The reactionmixture was stirred for 1 hour during which a precipitate forms. Next28% aq. ammonium hydroxide (NH₄OH, 35 mL, 2.86 eq.) was added. Thereaction mixture was stirred overnight. The next morning the layers wereseparated and the CPME layer was washed with 0.5M aq. H₂SO₄ (105 mL,0.5M aq. K₂CO₃ (105 mL) and brine (70 mL), respectively. The CPMEsolution was dried over MgSO₄ and concentrated to dryness under vacuumto afford crude amide A-d. GCMS: 221 (M+).

Alternative reagents and reactions conditions to those disclosed abovemay also be employed. For example, ethereal solvents (e.g., THF, MeTHF,or MTBE) and temperatures ranging from about 0° C. to about 60° C. maybe used. In addition, other ammonia sources (e.g., liquid ammonia) maybe used. Further, other activating agents, such as any peptide couplingagent (e.g., T3P), or chlorinating reagent (e.g., thionyl chloride) maybe employed.

Synthesis of A-e from A-d

Crude amide A-d was taken up in methanol (MeOH, 262 mL, 7.5 mL/g) andtrichloroisocyanuric acid (TCCA, 8.65 g, 0.38 eq.) was added followed byslow addition of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 35 mL, 2.4eq.) in such a rate so as to not exceed 40° C. After about 1 hour thetemperature was increased to about 65° C. and the reaction mixture washeld at this temperature for 20 hours. Next, MeOH was removed viadistillation under vacuum. The residue was diluted with isopropylacetate (IPAC, 175 mL) and 1M aq. KH₂PO₄ (175 mL). After vigorouslystirring for 15 minutes the solids were removed via filtration throughdiatomaceous earth followed by a rinse with IPAC (35 mL). The layers ofthe filtrate were separated. The IPAC layer was washed with brine (70mL, 2 mL/g) followed by drying over MgSO₄ and concentrated to drynessunder vacuum to afford carbamate A-e. GCMS: 223 (M+).

Alternative reagents and reactions conditions to those disclosed abovemay also be employed. For example, other methanolic mixtures withnon-protic solvents (e.g., THF, MeTHF, or MTBE) and temperatures rangingfrom about 0° C. to about 60° C. may be used. In addition, otherhalogenating reagents (e.g., chlorine, bromine, NBS, or NCS) and stronghindered organic bases (e.g. DIPEA) may be used.

Synthesis of A-f from A-e:

The residue containing crude carbamate A-e was taken up in isopropylacetate (70 mL) followed by addition of di-tert-butyl dicarbonate(Boc₂O, 21.4 g, 1.0 eq.) and DMAP (598 mg, 0.05 eq.). The reactionmixture was stirred for about 20 hours. The reaction mixture wasconcentrated to dryness under vacuum to afford bis-carbamate A-f. GCMS:257 (M-tBu), 223 (M-Boc).

Alternative reagents and reactions conditions to those disclosed abovemay also be employed. For example, non-protic solvents (e.g., THF,MeTHF, MTBE, or toluene) and temperatures ranging from about 0° C. toabout 60° C. may be used. In addition, hindered organic bases (e.g.,DIPEA) may be employed.

Synthesis of V-v from A-f

The residue containing bis-carbamate A-f was taken up in IPA (100 mL,2.5 mL/g) followed by addition of 2M aq. KOH (100 mL). After stirringovernight, 2M aq. HCl (100 mL) was added followed by CPME (100 mL). Thelayers were separated. The CPME layer was extracted twice with 1M aq.NaOH (35 mL). Both aqueous layers were combined followed addition of IPA(70 mL) and 1M aq. HCl (70 mL). After stirring overnight the resultingsuspension was filtered and the solids (racemic V-v) were washed with50% aq. IPA (35 mL). The filtrate was extracted with IPAC (100 mL). TheIPAC layer was dried over Na₂SO₄ and concentrated to dryness undervacuum. The residue was taken up in heptane and concentrated to drynessunder vacuum. The residue was taken up in THF (25 mL) and 1M aq. NaOH(25 mL) followed by addition of Boc₂O (21.4 g, 1.0 eq.). The reactionmixture was stirred overnight. Next morning IPAC (25 mL) and water (25mL) was added. The layers were separated. The IPAC layer was extractedwith 0.5M aq. K₂CO₃ (12.5 mL). Both aqueous layers were combined andIPAC (25 mL) was added followed by acidification with 1M aq. HCl to pH˜2. The layers were separated. The IPAC layer was washed with water (25mL). Next the IPAC layer was dried over Na₂SO₄ and concentrated todryness under vacuum. The residue was taken up in IPAC (10 mL) andhexane (200 mL) were added slowly. The resulting suspension was stirredfor a few hours. The solids were collected via filtration, rinsed withhexane and dried at about 40° C. in a vacuum oven to afford V-v (6.8 g).

Alternative reagents and reactions conditions to those disclosed abovemay also be employed. For example, other alcohol solvents (e.g.,methanol, or ethanol) and temperatures ranging from about 0° C. to about60° C. may be used. In addition, other hydroxide sources (e.g., LiOH, ortetrabutylammonium hydroxide) may be employed.

In the second alternative scheme, racemic A-b was selectively hydrolyzedto racemic (±)-A-c. This mono acid (±)-A-c was subjected to form a saltA-g with dicyclohexylamine. This salt was then freebased and subjectedto a classical resolution by converting to the cinchonidine salt A-h.Curtius rearrangement of A-h followed by hydrolysis affordedintermediate V-v which was then converted to XII as shown in the abovescheme.

Second Alternative Scheme for Intermediate V-v Used to Synthesize XII

Hydrolysis of A-b to (±)-A-c

To the solution of A-b was charged isopropanol (250 mL), and thesolution was cooled to between about −15 and about −10° C. To this wasadded tetraethylammonium hydroxide (35 wt % in H₂O, 365.2 g, 0.88 moles,2.2 equiv) over at least about two hours, maintaining a temperaturebelow about −10° C. After stirring between about −15 and about −10° C.for about 12 hours until reaction completion, toluene (250 mL) and water(200 mL) were added, maintaining the temperature below about 0° C. Thismixture was stirred at about −5-0° C. for about 15 minutes, then warmedto about 20° C. to about 25° C. This mixture was stirred at about 20° C.to about 25° C. for about 15 minutes, and the phases were allowed toseparate for 30 minutes.

The aqueous layer was transferred to a second reactor and toluene (150mL) was added. This mixture was stirred at about 20° C. to about 25° C.for about 15 minutes, and the phases were allowed to separate for about30 minutes. The phases were split, and toluene (400 mL) was added to theaqueous layer. The mixture was cooled to about 10° C., and 50% aq. H₂SO₄(ca. 20 mL) was added, maintaining the temperature below about 15° C.until about pH 2-3 achieved. This mixture was stirred at about 10° C.for about 15 minutes, and the phases were allowed to separate for about30 minutes. The organic layer was assayed, and the volume reduced fromapproximately 550 mL to 80 mL by vacuum distillation at about 40° C. toabout 45° C. to provide A-c.

Alternative reagents and reactions conditions to those disclosed abovemay also be employed. For example, other bases (e.g. sodium hydroxide,potassium hydroxide, lithium hydroxide, tetrabutylammonium hydroxide,tetramethylammonium hydroxide, tetrapropylammonium hydroxide, potassiumphosphate dibasic, potassium carbonate, sodium carbonate) may be used.In addition, other solvents (e.g. cyclopentyl methyl ether, methyltert-butyl ether, dichloromethane, chloroform, chlorobenzene,tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, methanol,ethanol, tert-butanol) may be employed. Also, temperatures ranging fromabout −15° C. to about −10° C. may be used.

Synthesis of A-g from (±)-A-c

To the toluene solution from above was added toluene (54 mL). Then,maintaining the temperature below about 40° C., dicyclohexylamine (26.2g, 140 mmol, 0.36 equiv) was added. The mixture was heated to 75° C.until dissolution achieved. The mixture was cooled to about 65° C. toallow crystallization, then stirred at about 65° C. for about 30minutes, then cooled to about 0° C. over three hours. The slurry wasstirred at about 0° C. for about two hours, then filtered. The filtercake was washed three times with 10:1 heptane:toluene (20 mL), and thesolids dried at about 40° C. under vacuum to provide A-g. ¹H NMR (400MHz, CDCl₃): δ 1.18-1.26 (m, 12H), 1.28-1.33 (m, 1H), 1.39-1.48 (m, 5H),1.65 (d, J=8 Hz, 2H), 1.79 (d, J=12 Hz, 4H), 1.99 (d, J=11.6 Hz, 4H),2.1-2.2 (m, 1H), 2.95 (tt, J=8 Hz and 3.6, 2H), 5.03 (septet, J=6 Hz,1H), 5.63 (td, J=56.4 and 5.6, 1H). ¹⁹F NMR (376 MHz, CDCl₃): δ −113(ddd, J=2326 Hz, 285 Hz and 8.3 Hz).

Alternative reagents and reactions conditions to those disclosed abovemay also be employed. For example, other solvents (e.g. dichloromethane,chloroform, chlorobenzene, methyl tert-butyl ether, cyclopentyl methylether, 2-methyltetrahydrofuran, hexanes, cyclohexane) may be employed.

Alternative reagents and reactions conditions to those disclosed abovemay also be employed. For example, other solvents (e.g. dichloromethane,chloroform, chlorobenzene, MTBE, cyclopentyl methyl ether,2-methyltetrahydrofuran, hexanes, cyclohexane) may be employed.

Synthesis of A-h from A-g

Solid A-g (444.8 g, 1.10 moles) was charged to a 5-L reactor under N₂.To this was added methylisobutyl ketone (MIBK, 2200 L) followed by 1 MH₃PO₄ (2200 ml), and the layers were agitated for about 15 minutes andseparated. The organic layer was washed with water (1 L). Concentratethe reaction contents by distilling ˜500 ml of solvent (including H₂O).The solution was filtered through diatomaceous earth.

Cinchonidine (304.5 g, 1.03 moles, 1.0 equiv.) was added to the reactor,along with MIBK (2500 ml). To this suspension was added the MIBKsolution of (±)-A-c (in 2000 ml MIBK). The reaction mixture was heatedto about 50° C. A-h (534 mg, 0.1 wt %) was added as seed, then themixture was treated with the following temperature program: about 50° C.for about 1 hr, heated to about 60° C. over about 30 minutes, aged atabout 60° C. for about 3 hrs, cooled to about 58° C. over about 4 hrs,cooled to about 50° C. over about 4 hrs, cooled to about 40° C. overabout 2 hrs, cooled to about 20° C. over about 2 hrs, held at about 20°C. for about 2 hrs. The slurry was filtered. The cake was washed withMIBK (400 ml). The material was dried in a vacuum oven.

The resulting solids were added to a 5-L reactor under N₂, followed byMIBK (1438 ml, 7V) and methanol (144 ml, 0.7V) The resulting slurry washeated to about 60° C. to achieve a solution, then seeded with 0.1 wt %A-h. The light suspension was maintained at about 60° C. for about threehours, then underwent parabolic cooling to about 20° C. and held atabout 20° C. for about five hours. Next, MIBK (200 mL, 1V) was added,and the slurry distilled under vacuum to about 6.5-7V to remove MeOH.Once the MeOH content was below 0.5%, the slurry was cooled to about 5°C. over about 2.5 hours and held at about 5° C. for about one hour. Theslurry was filtered and the cake washed three times with MIBK (150 mL,0.7V). The material was dried in a vacuum oven to afford A-h. ¹H NMR(400 MHz, CDCl₃): δ 1.24 (t, J=6 Hz, 7H), 1.41-1.45 (m, 1H), 1.52 (t,J=5.6 Hz, 1H), 1.70-1.80 (m, 1H), 2.02 (m, 1H), 2.10 (m, 1H), 2.20-2.30(m, 1H), 2.60 (bs, 1H), 3.03 (td, J=13.6 Hz and 4.4 Hz 1H), 3.10-3.16(m, 1H), 3.33 (dt, J=10.4 Hz and 3.2 Hz, 2H), 4.30 (m, 1H), 4.98-5.00(m, 1H), 5.08 (septet, J=6.4 Hz, 1H), 5.48-5.55 (m, 1H), 5.69 (td,J=56.8 Hz and 5.2 Hz, 1H), 6.26 (s, 1H), 7.46 (t, J=8 Hz, 1H), 7.63 (t,J=8 Hz, 1H), 7.69 (d, 4.4 Hz, 1H), 7.92 (d, 8.4 Hz, 1H), 8.03 (d, J=8Hz, 1H), 8.86 (d, J=4.4 Hz, 1H). ¹⁹F NMR (376 MHz, CDCl₃): δ −113 (ddd,J=2435 Hz, 286 Hz and 7.1 Hz).

Alternative reagents and reactions conditions to those disclosed abovemay also be employed. For example, other acids (e.g. sulfuric acid) maybe employed and other solvents (e.g. isopropyl acetate, MTBE) may beemployed.

Curtius Rearrangement of A-h to A-i

In a reaction vessel, was charged A-h (200 g, 387 mmole) and 15% aq.H₃PO₄ (800 mL, 4 mug). To the resulting suspension was added MTBE (400mL, 2 ml/g) and an exotherm from about 22° C. to about 25° C. wasobserved. Within about 5 minutes all the solids were dissolved. Afterabout 15 minutes stirring was discontinued and the layers were allowedto separate for about 10 minutes. The bottom layer (˜880 mL; pH ˜2.5;aq. layer 1) was removed. Stirring was resumed followed by addition ofwater (400 mL, 2 ml/g). Stirring was discontinued after about 15 minutesand the layers were allowed to separate for about 10 minutes. The bottomlayer (˜400 mL; ph ˜2.5; aq. layer 2) was removed. Stirring was resumedfollowed by addition of toluene (400 mL, 2 mL/g). The volume was reducedunder vacuum to 300 mL (1.5 mL/g; 40 torr, jacketed temperature up toabout 50° C. ˜575 mL distillate; distillate 1). The KF was checked anddeemed acceptable (32 ppm; <100 ppm).

To a reaction vessel, was charged DMAP (94.5 g, 774 mmol, 2 equiv.) andtoluene (300 mL, 1.5 mL/g) followed by DPPA (125 mL, 581 mmol, 1.5 eq.).The resulting suspension was heated to about 85° C. The hazy product intoluene solution was polish filtered into the hot DMAP/DPPA suspensionin such a rate to maintain the temperature between about 80° C. andabout 100° C. This was followed by a rinse with toluene (100 mL, 0.5mL/g). Upon completion of the addition, the reaction contents werecooled to about 80° C. to about 83° C. tBuOH (65.5 mL, 774 mmol, 2equiv) was added. The reaction mixture was aged for about 6 hours atabout 75° C. to about 80° C. The reaction mixture was cooled to about20° C. followed by addition of water (400 mL, 2 mL/g) which resulted inan exotherm up to about 23° C. Stirring was discontinued after about 15minutes and the layers were allowed to separate for about 15 minutes.The bottom layer (˜600 mL, pH ˜9; aq. layer 3) was removed. Stirring wasresumed and water (200 mL, 1 mL/g) was added. After about 10 minutesstirring was discontinued and the layers were allowed to settle forabout 10 minutes. The bottom layer (˜200 mL, pH ˜9; aq. layer 4) wasremoved. Stirring was resumed and the volume was reduced to 300 mL (1.5mL/g) via distillation. The resulting solution was cooled to about 20°C.

Alternative reagents and reactions conditions to those disclosed abovemay also be employed. For example, other acids (e.g. sulfuric acid) maybe employed and other bases (e.g. diisopropylethylamine, triethylamine)may be employed. Also, temperatures ranging from about 70° C. to 100° C.may be used.

Hydrolysis of A-i to V-v

To a reaction vessel were charged MeOH (300 mL, 1.5 mL/g) and powderedKOH (43.4 g, 774 mmol, 2 equiv). After the exotherm subsided theresulting hazy solution was added into the two liter reactor whichresulted in an exotherm up about 40° C. After about 3 hours the reactionwas deemed complete.

At this point, 15% aq. H₃PO₄ (600 mL, 3 mL/g) was added which resultedin an exotherm up to about 32° C. and a pH of about 2.5. After about 10minutes the resulting suspension was filtered followed by a rinse withMTBE (200 mL, 1 mL/g). The filtrate was stirred for about five minutesfollowed by discontinuation of stirring. The layers were allowed toseparate for about five minutes. The bottom layer (˜900 mL, pH ˜2.5; aq.layer 5) was removed. Stirring was resumed and water (200 mL, 1 mL/g)was added. After about five minutes stirring was discontinued and thelayers were allowed to separate for about 5 minutes. The bottom layer(˜250 mL, pH ˜2.5; aq. layer 6) was removed. Stirring was resumed andtoluene (400 mL, 2 mL/g) was added. The volume was reduced to 300 mL(1.5 mL/g) via distillation. The resulting solution was stirred at about20° C. and within about 1 hour a suspension is formed. After about 3hours heptane (300 mL, 1.5 mL/g) was slowly added over about 30 minutes.The resulting suspension was stirred overnight followed by cooling toabout 5° C. The solids were obtained via filtration. The mother liquorwas used for rinsing and the rinse was added the filter cake. After thefilter cake was pulled dry a rinse with 40% toluene in heptanes (100 mL,0.5 mL/g) was added to the filter cake followed by pulling this rinsethrough the filter cake. The solids were dried at about 40° C. in avacuum oven afford V-v. ¹H NMR (400 MHz, CD₃OD): δ 1.43 (s, 10H),1.64-1.80 (m, 1H), 1.89-2.00 (m, 1H), 5.87 (td, J=53.6 Hz and 7.2 Hz,1H). ¹⁹F NMR (376 MHz, CDCl₃): δ −113 (m).

Assembly Steps of Route I to Compound of Formula I

A. Synthesis of Compound of Formula III (R═CH₃)

I. Free-basing and Boc-protection of II (R═CH₃) to Provide III (R═CH₃):

II (10.1 g, 29.3 mmol, 1.00 equivalents) was combined withdichloromethane (40 mL) and the mixture stirred at about 20 to about 25°C. Triethylamine (8.36 g, 82.6 mmol, 3.00 equivalents) was addeddropwise via syringe, maintaining a reaction temperature of about 20° C.to about 25° C. To the resultant solution was charged4-dimethylaminopyridine (360 mg, 2.95 mmol, 0.1 equivalent) followed bya solution of di-tert-butyl dicarbonate (6.52 g, 29.9 mmol, 1.02equivalent) in dichloromethane (40 mL), while maintaining a reactiontemperature of about 20° C. to about 25° C. The mixture was stirred forabout 2-4 hours and monitored for completion. Upon reaction completion,100 mL of 1.0 N HCl was charged dropwise, while maintaining a reactiontemperature below about 30° C. The biphasic mixture was vigorouslystirred for about 15 minutes followed by allowing the layers toseparate. The bottom organic layer was partitioned and washedsuccessively with 5% wt/wt aqueous sodium bicarbonate (100 mL) and water(100 mL). The organic phase was concentrated under reduced pressure anddried under vacuum to afford III (R═CH₃). ¹H NMR (300 MHz, CD₃OD): δ4.41 (d, J=6.0 Hz, 1H), 4.01-4.07 (m, 1H), 3.65-3.79 (m, 4H), 3.05-3.15(m, 1H), 2.10-2.20 (m, 1H), 1.50-1.60 (m, 1H), 1.39-1.45 (app d, 9H),1.10-1.20 (m, 2H), 0.99-1.08 (m, 3H). ¹³C NMR (75 MHz, CDCl₃): δ 12.3,21.3, 28.2, 50.5, 50.6, 51.4, 52.2, 61.8, 71.9, 80.2, 154.2, 171.9.

Alternative reagents and reactions conditions to those disclosed abovemay also be employed. For example, amine bases (e.g.,diisopropylethylamine, or sodium hexamethyldisilizide), carbonates(e.g., potassium, or cesium carbonate), bicarbonates (e.g., sodiumbicarbonate), or inorganic/organic hydroxides (e.g., sodium hydroxide,or tetramethylammonium hydroxide) may be employed. In addition, otherBoc-delivery agents (e.g., BOC—ON═C(CN)Ph, BOC—ONH₂,1,2,2,2-tetrachloroethyl tert-butyl carbonate, or1-(t-butoxylcarbonyl)benzotriazole) and promoters (e.g., imidazole, orultrasound) can be used. Further, other organic solvents (toluene,acetonitrile, or acetone), water, polar aprotics (e.g.,N,N-Dimethylformamide (DMF) or dimethyl sulfoxide (DMSO), orcombinations of these with water), alcohols (e.g., methanol or ethanol),ethers (e.g., tetrahydrofuran, dioxane or methyl-t-butyl ether), oresters (e.g., ethyl acetate) can be used.

B. Synthesis of Compound of Formula V (R═CH₃)

II. S_(N)Ar Reaction of IV with III (R═CH₃) to Form V (R═CH₃)

Into a reactor containing III (R═CH₃) (1.00 equivalent) inN,N-dimethylacetamide (6 volumes) was charged IV (1.00 equivalent) andcesium carbonate (1.20 equivalents) under nitrogen atmosphere. Theheterogeneous reaction was heated to about 100 to 110° C. with stirring.Upon reaction completion, the reaction mixture was then cooled down toabout 20° C. and MTBE (10 volumes) was charged. The resulting mixturewas washed twice with water (6 volumes) and the MTBE solvent was swappedwith isopropanol (6 volumes) via vacuum distillation. The solution wasthen heated to about 60° C. and water (3 volumes) slowly added overabout 1.5 hours. Once the addition was complete, the mixture was held atabout 60° C. for about 30 minutes. A small amount of V (R═CH₃) (1-2wt/wt %) were then charged after which the temperature was slowly cooledto room temperature over about 3 hours. The contents were then aged forat least about 12 hours after which the slurry was filtered over theappropriate filter. The wet cake was washed with 2:1 isopropanol/water(3.5 volumes), followed by two water washes (3.5 volumes) and oven driedunder vacuum at about 40 to 45° C. ¹H NMR (400 MHz, CDCl₃): δ 7.93-7.90(m, 1H), 7.25-7.22 (m, 1H), 7.20-7.16 (m, 1H), 5.95-5.85 (m, 1H),5.44-5.38 (m, 1H), 5.25-5.21 (m, 2H), 4.54-4.52 (m, 1H), 4.47-4.40 (m,1H), 3.97 (s, 3H), 3.77 (s, 3H), 3.43-3.39 (m, 1H), 3.27-3.17 (m, 2H),2.79-2.68 (m, 1H), 1.64-1.55 (m, 1H), 1.44-1.43 (m, 9H), 1.44-1.32 (m,1H), 1.10-1.06 (m, 3H). LCMS (M+1): 521.97.

Alternative reagents and reactions conditions to those disclosed abovemay also be employed. For example, other inorganic bases (e.g., sodiumcarbonate (Na₂CO₃), potassium carbonate (K₂CO₃), potassium-tert-butoxide(KOtBu), lithium-tert-butoxide (LiOtBu), magnesium-tert-butoxide(Mg(OtBu)₂), sodium-tert-butoxide (NaOtBu), sodium hydride (NaH),potassium hexamethyldisilizide (KHMDS), potassium phosphate (K₃PO₄),potassium hydroxide (KOH), or lithium hydroxide (LiOH)) or organic bases(e.g., DABCO, or DBU) may be used. In addition, aprotic solvents (e.g.N,N-dimethylformamide (DMF), N-methyl-2-pyrrolidinone (NMP),dimethylsulfoxide (DMSO), acetonitrile (MeCN), or acetone), aproticsolvents with small amounts of added water added, ethers (e.g.,tetrahydrofuran (THF), or 1,4-dioxane), or toluene in the presence ofphase-transfer catalyst may be used. Further, other additives (e.g.,tetra-n-butyl ammonium bromide (TBAB), tetra-n-butylammonium iodide(TBAI), tetra-n-butylammonium chloride (TBACl), sodium iodide (NaI), ortetra-n-butylphosphonium bromide (TBPB)) and temperatures ranging fromabout 20° C. to about 120° C. may be used.

C. Synthesis of Compound of Formula VI (R═CH₃) Tosylate Salt

I. Boc Deprotection of V (R═CH₃) to Provide VI (R═CH₃)

V (R═CH₃) (50.0 g, 95.9 mmol, 1.00 equivalents) is combined with methyltetrahydrofuran (150 mL, 3.0 volumes) and the mixture was agitated atabout 15 to 25° C., preferably about 20° C. Para-toluenesulfonic acid(45.6 g, 240 mmol, 2.50 equivalents) in methyl tetrahydrofuran (100 mL,2.0 volumes) was charged to the reaction mixture. Once the acid additionwas complete, the contents were heated to about 50 to 60° C. and thereaction contents were agitated for about 3 to 5 hours. Upon reactioncompletion, MTBE (100 mL, 2 volumes) was added slowly to the slurry. Thecontents were then cooled to about 15 to 25° C., and the slurry wasfiltered and washed with a mixture of methyl tetrahydrofuran (105 mL,2.1 volumes) and MTBE (45 mL, 0.9 volumes). The solids were placed in avacuum oven to dry at about 35 to 45° C. ¹H NMR (400 MHz, CDCl₃) δ 10.33(s, 1H), 9.58 (s, 1H), 7.92 (d, J=9.2 Hz, 1H), 7.72 (d, J=8.1 Hz, 2H),7.31-7.21 (m, 1H), 7.11 (t, J=5.7 Hz, 3H), 5.97-5.77 (m, 1H), 5.49 (t,J=7.1 Hz, 1H), 5.19 (dd, J=27.6, 13.7 Hz, 2H), 4.73 (dd, J=12.1, 5.7 Hz,1H), 4.49 (dd, J=11.8, 6.4 Hz, 1H), 3.93 (d, J=9.1 Hz, 3H), 3.77 (s,3H), 3.60 (dd, J=13.2, 3.5 Hz, 1H), 3.17 (td, J=16.8, 7.0 Hz, 2H), 2.84(dd, J=14.1, 6.9 Hz, 1H), 2.30 (s, 3H), 1.67-1.34 (m, 2H), 1.05 (t,J=7.4 Hz, 3H). LC/MS: M/Z=422.2.

Alternative reagents and reactions conditions to those disclosed abovemay also be employed. For example, other acids (e.g., hydrochloric acid,or methanesulfonic acid) can be used. In addition, other organicsolvents (e.g., isopropyl acetate) may be employed.

D. Synthesis of Compound of Formula VIII (R═CH₃)

I. Salt Break of VII to Provide VII Free-Acid

VII (33.0 g, 87.6 mmol, 1.0 equivalents) was combined with MTBE (198 mL,6.0 volumes) and the resulting suspension was agitated. A solution ofconcentrated hydrochloric acid (33 mL, 1.0 volume) and water (165 mL,5.0 volumes) was charged to the suspension at a rate that maintained areaction temperature of about 15 to 25° C. As the acid was added, thesuspension became a biphasic solution. The resulting reaction mixturewas agitated for about 1 hour at about 15 to 25° C. Agitation wasstopped and the layers separated for about 15 minutes before the aqueouslayer was removed. Water (330 mL, 10 volumes) was added to the organicand was agitated for a about 15 min at about 15 to 25° C. Agitation wasstopped and the layers separated for about 15 minutes before the aqueouslayer was removed. Water (330 mL, 10 volumes) was added to the organicand was agitated for a about 15 min at about 15 to 25° C. Agitation wasstopped and the layers separated for about 15 minutes before the aqueouslayer was removed. A solution of 10 wt. % sodium chloride in water (300mL, 9 volumes) was added to the organic and the mixture was agitated forabout 15 min at about 15 to 25° C. Agitation was stopped and the layerswere separated for about 15 minutes before the aqueous layer wasremoved. The resulting organic layer was then concentrated to theminimum volume and was diluted with dimethylformamide (297 mL, 9.0volumes). The final solution was removed and polish filtered.

Alternative reagents and reactions conditions to those disclosed abovemay also be employed. For example, other acids (e.g., sulfuric acid, orphosphoric acid) may be used. Further, other organic solvents (e.g.,methyl-THF, or ethyl acetate) can be used.

II. Amide Coupling of VI (R═CH₃) and VII (Free Acid) to Provide VIII(R═CH₃)

VII (free acid) (40.0 g; 67.4 mmol; 0.77 eq.), EDC.HCl (16.8 g, 87.6mmol, 1.0 eq.), and HOBt monohydrate (13.4 g, 87.6 mmol, 1.0 eq) werecombined in a reaction vessel. The previously prepared VII (free acid)in DMF solution was charged to the solids, rinsed forward with DMF (39.6mL, 1.2 vol) and agitated to form a solution. The reaction mixture wascooled to about 0 to 10° C. before NMM was charged (19.3 mL, 175 mmol,2.0 eq.). The contents are agitated at about 0 to 10° C. for no lessthan about 1 hour. The reaction mixture was then adjusted to about 15 to25° C. and agitated until reaction was complete by LC analysis Uponreaction completion, toluene (429 mL, 13 volumes) was charged to thereactor and the temperature adjusted to about −5 to 5° C. Water (198 mL,6 volumes) was slowly charged to maintain a reaction temperature betweenabout 0 and 25° C. After water addition was complete, the contents wereadjusted to about 15 to 25° C. Agitation was stopped and the contentssettled for no less than 15 minutes before the aqueous layer wasremoved. A solution of potassium carbonate (20.6 g, 149 mmol, 1.7equivalents) in water (181 mL, 5.5 volumes) was charged to the organicphase and the resulting solution permitted to and agitate for about 15minutes before the agitation was stopped and the contents were allowedto settle for about 15 minutes. The aqueous basic layer was removed.Water (181 mL, 5.5 volumes) was charged to the organic phase andagitated for about 15 minutes before the agitation was stopped and thecontents allowed to settle for about 15 minutes. The aqueous basic layerwas removed. The organic phase was again partitioned between water (181mL 5.5 volumes) and agitated for about 15 minutes before agitation wasstopped and the contents allowed to settle for about 15 minutes. Theaqueous basic layer was removed. A solution of sodium chloride (20.5 g;350 mmol 4.00 equivalents) in water (181 mL; 5.5 volumes) was charged tothe organic and agitated for about 15 minutes before agitation wasstopped and the contents settled for about 15 minutes. The aqueousacidic layer was removed. The organic was concentrated to minimumstirring volume and was removed and polish filtered.

¹H NMR (400 MHz, CDCl3) δ 8.01 (d, J=9.1 Hz, 1H), 7.19-7.34 (m, 3H),6.09-5.78 (m, 2H), 5.55-5.21 (m, 3H), 5.06 (dd, J=32.9, 13.4 Hz, 2H),4.92 (d, J=8.5 Hz, 1H), 4.59 (dd, J=10.7, 6.3 Hz, 1H), 4.35 (d, J=9.7Hz, 1H), 4.11-3.92 (s, 3H), 3.95-3.87 (m, 1H), 3.85 (d, J=28.1 Hz, 3H),3.78-3.70 (m, 1H), 3.37-3.17 (m, 2H), 2.81-2.69 (m, 1H), 2.18-2.06 (m,1H), 1.95 (d, J=7.4 Hz, 1H), 1.63 (dd, J=14.4, 7.3 Hz, 1H), 1.48 (dd,J=14.4, 7.2 Hz, 1H), 1.17 (t, J=7.4 Hz, 3H), 1.12 (s, 9H), 0.84 (s, 1H),0.54 (d, J=6.4 Hz, 1H). LC/MS: m/z=659.

Alternative reagents and reactions conditions to those disclosed abovemay also be employed. For example, other coupling agents (e.g.1-hydroxy-7-azabenzotriazole) and base (e.g. pyridine, morpholine, orimidazole) may be employed. In addition, other organic solvents (e.g.,dimethylacetamide or acetonitrile) can be used.

E. Synthesis of compound of Formula IX (R═CH₃)

Ring Closing Metathesis of VIII (R═CH₃) to Provide IX (R═CH₃):

VIII (R═CH₃) (33 g of a 14.3 wt. % solution in toluene, 7.1 mmol, 1.00equivalents) and toluene (27 mL) were combined and the mixture wasagitated and heated to reflux (110° C.) and held at reflux temperaturefor about 3 to 5 hours. Separately, toluene (20 mL) was charged to areaction vessel. and degassed vigorously. Zhan 1B catalyst (173 mg, 0.24mmol, 0.033 equivalents) was charged and the mixture is agitated atabout 20 to 25° C. for about 60 minutes to obtain a homogenous solution.The toluene solution of Zhan catalyst was added to the refluxing toluenesolution of VIII (R═CH₃) over about 2 hours, maintaining a reactiontemperature of about 111° C. Upon reaction completion, the reaction wascooled to about 20° C. and 9.4 grams (2S) of silica gel was charged. Theslurry was vigorously agitated for about 4 hours and then filtered. Thereactor and filter were washed with isopropyl acetate (2×32 mL) and thefiltrate was concentrated to 50% volume (approximately 11 volumes). Tothis solution was charged 2.4 grams of activated charcoal (0.5 S). Theslurry was vigorously agitated for about 4 hours and then filtered. Thereactor and filter were washed with isopropyl acetate (2×16 mL) and thefiltrate was solvent exchanged to 5 volumes isopropyl acetate and useddirectly next step. ¹H NMR (300 MHz, CDCl₃): δ 7.95 (d, J=6.0 Hz, 1H),7.26 (m, 1H), 7.12 (m, 1H), 5.89 (m, 1H), 5.69 (m, 2H), 5.22 (d, J=9.0Hz, 1H), 4.77 (d, J=6.0 Hz, 1H), 4.40 (d, J=9.0 Hz, 1H), 4.29 (d, J=6.0Hz, 1H), 4.02-3.95 (m, 1H), 3.96 (s, 3H), 3.85 (m, 1H), 3.73 (s, 3H),3.21 (s, 2H), 2.90-2.70 (m, 1H), 2.49 (d, J=12.0 Hz, 1H), 1.41 (m, 2H),1.25-1.18 (m, 4H), 1.06 (s, 9H), 1.00-0.93 (m, 2H), 0.50 (m, 1H). LCMS:m/z=631.02.

Alternative reagents and reactions conditions to those disclosed abovemay also be employed. For example, other ruthenium-based Grubbs,Grubbs-Hoveyda, saturated and unsaturated imidazole and phosphine-basedcatalysts as well as Molybdenum-based catalysts, and variants thereof(for a representative, non-exhaustive list, see below, wherein Cy iscyclohexyl, Me is methyl, Ph is phenyl, and iPr is isopropyl) can beused.

In addition, other promoters (e.g., acetic acid, benzoquinones, CuI,CsCl, or Ti(O-i-Pr)₄), ethylene, or promoting conditions (e.g.,microwave irradiation) may be employed. Further, temperatures rangingfrom about 40° C. to 110° C. may be used. Other solvents, such ashalogenated (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene,or hexafluorobenzene), organic (e.g., benzene, THF, methyl-tert-butylether, cyclopentyl methyl ether, ethyl acetate, n-heptane, dimethylcarbonate, dimethyl formamide, acetonitrile), or alcohols (e.g.,methanol, isopropanol) may be used.

F. Synthesis of Compound of Formula X (R═CH₃)

Hydrogenation of IX (R═CH₃) to Provide X (R═CH₃):

IX (R═CH₃) in 5 volumes of iso-propyl acetate (IPAc) and Pt/C (5 wt %relative to IX (R═CH₃)) were charged to a reaction vessel. The reactorwas inerted with N₂, then evacuated and filled with H₂ to 5 psig. Themixture was stirred vigorously for about 12 to 24 hours under 5 psig H₂at room temperature. After completion of the reaction, diatomaceousearth (5 wt %) was charged, and mixture was filtered to remove thesolids, rinsing forward with additional IPAc. The IPAc solution wastreated with 6 volumes of 5% aqueous N-acetyl cysteine solution at about50° C. for overnight under N₂ with vigorous agitation. After cooling toroom temperature, the aqueous layer was removed and the organic layerwas rinse with 6 volumes of 5-10% aqueous NaHCO₃ and 6 volumes of 10%aqueous NaCl. Diatomaceous earth (0.5 S) was added, the mixture wasstirred for about 5 minutes, and the solids were subsequently removed byfiltration. The solution of X (R═CH₃) was carried on without furtherpurification.

¹H NMR (400 MHz, CDCl₃) δ 7.97 (d, J=9.2 Hz, 1H), 7.26 (dd, J=9.2, 2.7Hz, 1H), 7.09 (d, J=2.7 Hz, 1H), 5.88 (d, J=3.9 Hz, 1H), 5.29 (d, J=9.9Hz, 1H), 4.74 (d, J=7.2 Hz, 1H), 4.38-4.25 (m, 2H), 4.13-4.07 (m, 1H),3.94 (s, 3H), 3.78-3.76 (m, 1H), 3.71 (s, 3H) 2.63 (app dd, J=15.0, 7.5Hz, 1H), 2.54-2.32 (m, 1H), 2.02-1.98 (m, 1H), 1.84-1.63 (m, 4H),1.53-1.33 (m, 3H), 1.30-1.10 (m, 4H), 1.07 (s, 9H), 0.95-0.80 (m, 2H),0.77-0.64 (m, 1H), 0.46 (dd, J=12.9, 6.3 Hz, 1H). 19F NMR (376 MHz,CDCl3) δ −102.43 (ddd, J=250.4, 25.4, 8.6 Hz), −103.47 (ddd, J=250.4,28.7, 11.3 Hz).

Alternative reagents and reactions conditions to those disclosed abovemay also be employed. For example, other catalysts, such asheterogeneous metal catalysts (e.g., platinum, palladium, ruthenium, ornickel), metals on carbon, alumina, silica, and other heterogeneoussupports, metal nanoparticles, frustrated Lewis pairs (e.g., hydrogen[4-[bis(2,4,6-trimethylphenyl)phosphino]-2,3,5,6-tetrafluorophenyl]hydrobis(2,3,4,5,6-pentafluorophenyl)borate),homogeneous metal catalysts (e.g.,chlorotris(triphenylphosphine)rhodium(I), or(1,5-cyclooctadiene)(pyridine)(tricyclohexylphosphine)-iridium(I)hexafluorophosphate) can be used. In addition, water, protic solvents(e.g., methanol, ethanol, or acetic acid), aprotic solvents (e.g.,dimethyl sulfoxide, tetrahydrofuran, ethyl acetate, acetonitrile,toluene, dichloromethane or acetone), or combinations of the above maybe employed. Further, hydrogen gas at a range of pressures or formates(e.g., ammonium formate or formic acid) may be used. In addition,diimide and temperatures ranging from about −20° C. to about 150° C. maybe employed.

G. Synthesis of Compound of Formula XI (R═H) from X (R═CH₃)

II. Hydrolysis of X to Provide XI:

To solution of X (R═CH₃) in IPA (7 volumes) at about 30° C. under N₂ wasadded a solution of aqueous LiOH over about 5 to 10 minutes (1M, 2.3eq). The reaction mixture was warmed to an internal temperature of about40° C., and stirred. After cooling to room temperature MTBE (8 volumes)was added. The resulting mixture was acidified to pH 3 with 1M HCl. Theaqueous layer is removed and the organic layer is rinsed twice with 10%aqueous NaCl. Diatomaceous earth is added (0.1 S), and the resultingslurry is filtered, rinsing forward with additional MTBE. The MTBE isremoved via vacuum distillation, and the resulting solids are dissolvedin 5 volumes ethanol and 5 volumes heptane at about 60 to 65° C. Thesolution is then cooled to about 45 to 50° C. and seeded with a slurryof XI in ethanol/heptane (0.005 S). After stirring for about 6 hours atabout 45° C., the slurry is cooled to about 15° C. over about 10 hours.An additional 5 volumes heptane are added over about 1 hour. XI wasisolated via vacuum filtration and rinsed with 5 volumes 1:9EtOH:heptane. The resulting solids are dried in a vacuum oven at about40° C. to constant weight. ¹H NMR (400 MHz, CDCl₃) δ 7.95 (d, J=9.2 Hz,1H), 7.24 (dd, J=9.2, 2.6 Hz, 1H), 7.07 (d, J=2.6 Hz, 1H), 5.87 (d,J=3.5 Hz, 1H), 5.47 (d, J=9.9 Hz, 1H), 4.72 (d, J=7.2 Hz, 1H), 4.33 (d,J=12.2 Hz, 1H), 4.32 (d, J=9.9 Hz, 1H), 4.04 (dd, J=11.9, 4.0 Hz, 1H),3.93 (s, 3H), 3.7 (m, 1H), 2.64 (m, 1H), 2.43 (m, 1H), 1.99 (m, 1H),1.8-1.3 (m, 6H), 1.25-1.15 (m, 3H), 1.0 (m, 1H). ¹³C NMR (75 MHz,CDCl₃): δ 172.63, 171.64, 162.06, 157.49, 153.37, 142.42, 139.12 (dd,J_(CF)=30.6, 25.8 Hz), 133.06, 130.44, 120.1 (t, J_(CF)=245 Hz), 119.93,105.31, 77.45, 61.66, 59.49, 55.74, 54.98, 51.92, 46.52, 36.42 (t,J_(CF)=25.0), 34.91, 30.35, 27.74, 26.19, 21.53, 19.99, 18.34, 12.06,11.33.

Alternative reagents and reactions conditions to those disclosed abovemay also be employed. For example, carbonates (e.g., lithium, sodium, orcesium carbonates), metal hydrides (e.g., sodium hydride, or potassiumhydride), alkoxides (e.g., sodium methoxide, sodium tert-butoxide,lithium tert-butoxide, potassium tert-butoxide, or tetraalkylammoniumalkoxides), hydroxides (e.g., sodium hydroxide, potassium hydroxide, tinhydroxides, or tetraalkylammonium hydroxides), or amine bases, (e.g.,DBU) may be employed. In addition, protic acids (e.g., sulfuric acid,hydrochloric acid, p-toluene sulfonic acid, or solid-supported acids),Lewis acids (e.g., boron trifluoride), metal salts, metal complexes, orhydrogen-bond donors can be used. Further, polar protic solvents,including water, alcohols (e.g., methanol, ethanol, iso-propanol,tert-butanol, neopentyl alcohols, glycols, and combinations of thesewith water), polar aprotic solvents, (e.g., dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, 1,4-dioxane, or combinations of these withwater), or ionic liquids, (e.g., 3-methylimidazoliumhexafluorophosphate) may be employed.

H. Synthesis of Compound of Formula I from X (R═CH₃)

Synthesis of compound of formula I from X was similar to that describedin U.S. Publication No. 2014-0017198. X (R═CH₃) was hydrolyzed to formXI (R═H) which was coupled with XII to form I.

Alternative Route with t-Butyl Ester on Proline

An alternative scheme employing the t-butyl ester of the proline portionas was used in U.S. Publication No. 2014-0017198, but with the new RCMroute homologs of the proline and cyclopropyl-leucine portions. Thetert-butyl group can be removed by acid treatment after thehydrogenation stage.

Synthesis of Compound of Formula VI (R=tert-Bu),tert-Butyl(25,35,4R)-4-((3-(1,1-difluorobut-3-en-1-yl)-7-methoxyquinoxalin-2-yl)oxy)-3-ethylpyrrolidine-2-carboxylate

I. Boc Deprotection of V (R=tert-Bu) to Provide VI (R=tert-Bu)

V (R=tert-Bu) (0.88 g, 1.56 mmol, 1.0 eq.), t-BuOAc (9.5 mL, 11 vols.)and CH₂Cl₂ (2.4 mL, 2.7 vols.) were charged to a round bottom flaskequipped with a magnetic stir bar. Methanesulfonic acid was charged(0.51 mL, 7.8 mmol, 5.0 eq.) and the reaction mixture was stirredovernight at about 20° C. for about two hours. The reaction solution wasthen poured into 60 mL of a 1:1 saturated NaHCO₃/EtOAc mixture and theorganic layer was separated. The aqueous layer was subsequentlyback-extracted with EtOAc and the combined organics were washedsuccessively with saturated NaHCO₃ and brine followed by drying withmagnesium sulfate, filtering and concentrating to obtain VI (R=tert-Bu).LCMS: m/z=464.4.

Alternative reagents and reactions conditions to those disclosed abovemay also be employed. For example, other acids, such as inorganic (e.g.,hydrochloric acid) or organic (e.g., p-toluenesulfonic acid) may beused. In addition, other organic solvents (e.g., isopropyl acetate,methyl-t-butyl ether, or 2-methyl tetrahydrofuran) and temperaturesranging from about 50° C. to about 60° C. may be employed.

Synthesis of compound of formula VIII (R=tert-Bu),tert-Butyl(2S,3S,4R)-1-((S)-2-((((1R,2R)-2-allylcyclopropoxy)carbonyl)amino)-3,3-dimethylbutanoyl)-4-((3-(1,1-difluorobut-3-en-1-yl)-7-methoxyquinoxalin-2-yl)oxy)-3-ethylpyrrolidine-2-carboxylate

I. Amide Coupling of VI (R=Tert-Bu) and VII to Provide VIII (R=Tert-Bu)

VI (R=tert-Bu) (4.12 g, 8.9 mmol, 1.0 eq.), VII (2.72 g, 10.7 mmol, 1.2eq.) and acetonitrile (120 mL, 29 vols.) were charged to a flask. HATU(4.4 g, 11.6 mmol, 1.3 eq.) followed by DIPEA (6.2 mL, 35.6 mmol 4 eq.)were then charged. The reaction mixture was stirred overnight at about20° C. The reaction mixture was then concentrated and purified by silicagel flash column chromatography (eluent gradient of 0% to 18% to 25%ethyl acetate in hexanes) to obtain VIII. LCMS: m/z=701.1.

Alternative reagents and reactions conditions to those disclosed abovemay also be employed. For example, other coupling reagents (e.g.,ethyl-3-(3-dimethylaminopropyl) carbodiimide or hydroxybenzotriazolemonohydrate) can be used. In addition, other bases (e.g., pyridine,morpholine, imidazole, or N-methylmorpholine) and organic solvents(e.g., dimethylacetamide, or N,N-dimethylformamide) may be employed.

Synthesis of compound of formula IX (R=tert-Bu)tert-butyl(33R,34S,35S,91R,92R,5S)-5-(tert-butyl)-34-ethyl-14,14-difluoro-17-methoxy-4,7-dioxo-2,8-dioxa-6-aza-1(2,3)-quinoxalina-3(3,1)-pyrrolidina-9(1,2)-cyclopropanacyclotetradecaphan-11-ene-35-carboxylate

II. Ring Closing Metathesis of VIII (R=Tert-Bu) to Provide IX(R=Tert-Bu)

Zhan 1B catalyst (26 mg, 0.036 mmol, 0.025 equiv.) was charged to aflask. The flask was evacuated and back-filled with nitrogen threetimes. Nitrogen-sparged toluene (25 mL) was charged and the mixture wasagitated and heated to reflux (about 110° C.). A solution of compoundVIII (R=tert-Bu) (1.0 g, 1.4 mmol, 1.00 equivalents) in 5 mL toluene wasadded over 30 minutes, maintaining a reaction temperature of about 110°C. Upon reaction completion, the reaction mixture was cooled to about20° C. and purified by flash column chromatography (54 g silica gel, 20%ethyl acetate in hexane as eluent) to yield IX (R=tert-Bu). ¹H NMR (300MHz, CDCl₃): δ 7.95 (d, J=6.0 Hz, 1H), 7.26 (m, 1H), 7.12 (m, 1H), 5.89(m, 1H), 5.69 (m, 2H), 5.27 (d, J=9.0 Hz, 1H), 4.62 (d, J=6.0 Hz, 1H),4.35 (d, J=9.0 Hz, 1H), 4.29 (d, J=6.0 Hz, 1H), 4.02-3.95 (m, 1H), 3.96(s, 3H), 3.88 (m, 1H), 3.21 (s, 2H), 2.90-2.70 (m, 1H), 2.49 (d, J=12.0Hz, 1H), 1.48 (m, 9H), 1.41 (m, 2H), 1.25-1.18 (m, 4H), 1.06 (s, 9H),1.00-0.93 (m, 2H), 0.50 (m, 1H). ¹⁹F NMR (282.2 MHz, CDCl₃): δ −101.0ppm (m).

Alternative reagents and reactions conditions to those disclosed abovemay also be employed. For example, other ruthenium-based Grubbs,Grubbs-Hoveyda, saturated and unsaturated imidazole and phosphine-basedcatalysts as well as Molybdenum-based catalysts, and variants thereof(for a representative, non-exhaustive list, see below, wherein Cy iscyclohexyl, Me is methyl, Ph is phenyl, and iPr is isopropyl) can beused.

In addition, other promoters (e.g., acetic acid, benzoquinones, CuI,CsCl, or Ti(O-i-Pr)), or promoting conditions (e.g., microwaveirradiation, or ethylene) may be employed. Further, temperatures rangingfrom about 40° C. to 110° C. may be used. Other solvents, such ashalogenated (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene,or hexafluorobenzene), organic (e.g., benzene, THF, methyl tert-butylether, cyclopentyl methyl ether, ethyl acetate, n-heptane, dimethylcarbonate, dimethyl formamide, or acetonitrile), or alcohols (e.g.,methanol, isopropanol) may be used.

Example 2 Synthesis of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide(I) by route II

a. Hydrolysis, Ring Closing Metathesis and Hydrogenation:

Route II differs from route I of Example I in the order of assembly.Compound of formula VIII was hydrolyzed first to provide compound offormula XVIII and then subjected to the ring closing metathesis toprovide compound of formula XIX which on hydrogenation yielded compoundof formula XI. The reaction conditions for hydrolysis, ring closingmetathesis, and hydrogenation were similar to those disclosed in routeI. Compound of formula XI was converted to compound of formula I asdiscussed above in Example 1.

Example 3 Synthesis of(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide(I) by route III

Compound of formula I was synthesized via route III as shown below:

A. Synthesis of XV

Compound XIV (R═CH₃) (180 mg, 0.35 mmol, 1 equiv) and XIII (180 mg, 0.67mmol, 1.9 equiv) were dissolved in 15 volumes of degassed toluene (2.7mL). The system was inerted under nitrogen, and Zhan 1B catalyst (53 mg,0.073 mmol, 0.20 equiv.) was charged. The mixture was warmed to about95° C. and stirred for about 45 minutes. The reaction was cooled toabout 20° C., and purified by silica gel chromatography to provideintermediate XV (R ═CH₃). LCMS (M+1): 749 m/z. ¹H NMR (400 MHz, CDCl₃):δ 7.98-7.90 (m, 1H), 7.28-7.14 (m, 2H), 6.30-5.95 (m, 1H), 5.58-5.19 (m,3H), 4.56 (dd, 1H, J=36.8, 8.5 Hz), 4.46-4.24 (m, 1H), 4.22-4.01 (m,3H), 3.95 (s, 3H), 3.85-3.67 (m, 5H), 3.40-3.27 (m, 1H), 2.50-1.98 (m,4H), 1.65-1.55 (m, 1H), 1.43-1.41 (m, 9H), 1.1-0.7 (m, 11H), 0.57-0.40(m, 2H).

B. Hydrogenation of Intermediate XV (R═CH₃) and Hydrolysis of XVI(R═CH₃)

A mixture of intermediate XV (R═CH₃) (117 mg, 0.156 mmol) and Pt/C (13mg, 5 wt %) in 14 volumes of IPAc (1.6 mL) was stirred under 5 psig H₂at room temperature for 20 hours. The mixture was filtered throughdiatomaceous earth, concentrated in vacuo, and purified by silica gelchromatography to yield ˜75 mg of intermediate XVI (64% yield).Intermediate XVI was dissolved in 1 mL CH₂Cl₂, and combined with 0.5 mL4M HCl in dioxane at rt. After about 40 minutes, the mixture wasconcentrated to yield intermediate XVII, which was carried forwardwithout further purification.

C. Lactamization of(S)-2-((((1S,2S)-2-(5-(3-(((3R,4S,5S)-4-ethyl-5-(methoxycarbonyl)pyrrolidin-3-yl)oxy)-6-methoxyquinoxalin-2-yl)-5,5-difluoropentyl)cyclopropoxy)carbonyl)amino)-3,3-dimethylbutanoicacid hydrochloride (XVII (R═CH₃)) to form X (R═CH₃)

To a solution of XVII (20 mg, 0.029 mmol, 1 equiv) in 100V DMF (2 mL) atrt was added HOBt (39.3 mg, 0.29 mmol, 10 equiv), followed by EDC (56mg, 0.29 mmol, 10 equiv). The mixture was stirred for 5 minutes at whichpoint triethylamine (0.1 mL, 0.72 mmol, 25 equiv) was added. After 4.5hours, the mixture was diluted with MTBE, rinsed with twice withsaturated aqueous NH₄Cl, twice with saturated aqueous NaHCO₃, dried overMgSO₄, filtered, and concentrated in vacuo. The crude product thusobtained was diluted to 25 mL in a volumetric flask. UPLC analysisindicated the presence of X (R═CH₃) (10.6 mg, 59% assay yield).

However, alternative reagents and reactions conditions to thosedisclosed above may also be employed. For example, other couplingreagents (e.g., carbodiimidazole, N,N′-Dicyclohexylcarbodiimide,N,N′-Diisopropylcarbodiimide,benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate,1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate, or 2,4,6-trichlorobenzoyl chloride) may beused In addition, other bases, such as amine (e.g.,diisopropylethylamine, pyridine or sodium hexamethyldisilizide),carbonates (e.g., potassium, or cesium carbonate), bicarbonates (e.g.,sodium bicarbonate), or inorganic/organic hydroxides (e.g., sodiumhydroxide, or tetramethylammonium hydroxide) may be employed. Otherpromoters (e.g., 4-dimethylaminopyridine, or1-Hydroxy-7-azabenzotriazole) can be used. Further, other solvents, suchas water, polar aprotics (e.g., N,N-Dimethylformamide (DMF) and dimethylsulfoxide (DMSO) (or combinations of these with water), organics (e.g.,toluene, acetonitrile, or acetone), alcohols (e.g., methanol orethanol), ethers (e.g., tetrahydrofuran, dioxane or methyl-t-butylether), esters (e.g., ethyl acetate), or chlorinated solvents (e.g.,dichloromethane) may be employed.

Compound of formula X was converted to compound of formula I asdiscussed above in Example 1.

What is claimed is:
 1. A process for preparation of a compound offormula V:

or a salt thereof; comprising contacting a compound of formula III or asalt thereof, with a compound of formula IV:

under O-arylation conditions to provide the compound of formula V or asalt thereof, wherein R is C₁₋₆ alkyl, PG is a protective group, and R¹is a leaving group.
 2. A process for preparation of a compound offormula I:

or a pharmaceutically acceptable salt thereof; comprising: a) preparinga compound of formula V:

or a salt thereof according to the process of claim 1; b) subjecting thecompound of formula V or a salt thereof to N-deprotection conditions toprovide a compound of formula VI:

or a salt thereof; c) contacting the compound of formula VI or a saltthereof with a compound of formula VII:

or a salt thereof, under amide coupling conditions to provide a compoundof formula VIII:

or a salt thereof; d) performing ring closing metathesis of the compoundof formula VIII or a salt thereof to provide a compound of formula IX:

or a salt thereof; e) hydrogenating the compound of formula IX or aco-crystal, or a salt thereof in presence of a catalyst to provide acompound of formula X:

or a salt thereof; f) hydrolyzing the compound of formula X or a saltthereof to provide a compound of formula XI:

or a salt thereof; g) contacting the compound of formula XI or a saltthereof with a compound of formula

or a salt thereof; under amide coupling conditions to provide thecompound formula I:

or a pharmaceutically acceptable salt thereof, wherein R is C₁₋₆ alkyl,PG is a protective group, and R¹ is a leaving group.
 3. A process forpreparation of a compound of formula I:

or a pharmaceutically acceptable salt thereof, comprising: a) preparinga compound of formula V

or a salt thereof according to the process of claim 1; b) contacting thecompound of formula V or a salt thereof with an acid underN-deprotection conditions to provide a compound of formula VI:

or a salt thereof; c) contacting the compound of formula VI or a saltthereof with a compound of formula VII:

or a salt thereof, under amide coupling conditions to provide a compoundof formula VIII:

or a salt thereof; d) hydrolyzing the compound of formula VIII or a saltthereof to provide a compound of formula XVIII:

or a salt thereof; e) performing ring closing metathesis of the compoundof formula XVIII or a salt thereof in presence of a catalyst to providea compound of formula XIX:

or a salt thereof; f) hydrogenating the compound of formula XIX inpresence of a catalyst to provide a compound of formula XI:

or a salt thereof; g) contacting the compound of formula XI or a saltthereof with a compound of formula XII:

or a salt thereof; under amide coupling conditions to provide thecompound formula I:

or a pharmaceutically acceptable salt thereof, wherein R is C₁₋₆ alkyl,PG is a protective group, and R¹ is a leaving group.
 4. A process forpreparation of a compound of formula XV:

or a salt thereof, comprising contacting a compound of formula XIII:

or a salt thereof, with a compound of formula XIV:

or a salt thereof, under cross-metathesis conditions to provide thecompound of formula XV or a salt thereof, wherein R is C₁₋₆ alkyl and PGis a protective group.
 5. A process for preparation of a compound offormula I:

or a pharmaceutically acceptable salt thereof, comprising: a) preparinga compound of formula XV:

or a salt thereof according to the process of claim 4, b) hydrogenatingthe compound of formula XV or a salt thereof in presence of a catalystto provide a compound of formula XVI:

or a salt thereof; c) subjecting the compound of formula XVI or a saltthereof to N-deprotection conditions to provide a compound of formulaXVII:

or a salt thereof; d) contacting the compound of formula XVII with anamide coupling agent under lactamization conditions to give a compoundof formula X:

or a salt thereof; e) hydrolyzing the compound of formula X or a saltthereof to provide a compound of formula XI:

or a salt thereof; and contacting the compound of formula XI or a saltthereof with a compound of formula XII:

or a salt thereof under amide coupling conditions to provide thecompound formula I:

or a salt thereof, wherein R is C₁₋₆ alkyl and PG is a protective group.6. A process for preparation of a compound of formula V-v:

a salt thereof, comprising: hydrolyzing the compound of formula A-b:

or a salt thereof to provide a compound of formula A-c:

or a salt thereof; b) contacting the compound of formula A-c or a saltthereof with dicyclohexylamine to provide a compound of formula A-g:

or a salt thereof; c) contacting A-g or a salt thereof with cinchonidineto provide a compound of formula A-h:

or a salt thereof; d) subjecting A-h or a salt thereof to Curtiusrearrangement in presence of tert-butanol to provide a compound offormula A-i:

or a salt thereof; and e) hydrolysis of A-i or a salt thereof to provideV-v a salt thereof.